Oncogene (2004) 23, 6445–6470 & 2004 Nature Publishing Group All rights reserved 0950-9232/04 $30.00 www.nature.com/onc

Highly penetrant hereditary cancer syndromes

Rebecca Nagy*,1, Kevin Sweet1 and Charis Eng1

1Clinical Cancer Genetics Program and Human Cancer Genetics Program, Comprehensive Cancer Center, Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA

The past two decades have brought many important of cancer diagnosis than what is typically seen for that advances in our understanding of the hereditary suscept- cancer type; individuals with multiple primary cancers; ibility to cancer. Approximately 5–10%of all cancers are the occurrence of cancers in one family, which are inherited, the majority in an autosomal dominant manner known to be genetically related (such as breast and with incomplete penetrance. While this is a small fraction ovarian cancer, or colon and uterine cancer); and the of the overall cancer burden worldwide, the molecular occurrence of nonmalignant conditions and cancer in genetic discoveries that have resulted from the study of the same person and/or family (e.g. Marfanoid habitus families with heritable cancer have not only changed the and medullary thyroid cancer in multiple endocrine way these families are counselled and managed, but have neoplasia type 2B (MEN 2B)). Because of phenotypic shed light on molecular regulatory pathways important variability, age-related penetrance, and gender-specific in sporadic tumour development as well. In this review, we cancer risks, however, many families with an inherited consider 10 of the more highly penetrant cancer syn- cancer syndrome will not meet these criteria. Also, dromes, with emphasis on those predisposing to breast, because cancer is relatively common in the general colon, and/or endocrine neoplasia. We discuss the population, it is possible to have a chance clustering prevalence, penetrance, and tumour spectrum associated of the same or related cancers within a family. These with these syndromes, as well as their underlying genetic familial clusterings are most likely due to low-pene- defects. trance alleles that are more common than mutations Oncogene (2004) 23, 6445–6470. doi:10.1038/sj.onc.1207714 in genes such as BRCA1 or BRCA2. Thus, they will potentially account for a larger proportion of cancer in Keywords: inherited cancer susceptibility; familial cancer the general population than the rare, highly penetrant syndromes; breast cancer; colon cancer; endocrine alleles that are discussed here. Localization and char- neoplasia acterization of low-penetrance alleles are the focus of much research, but the challenges are great due to the multifactorial nature of cancer and the underlying genetic heterogeneity (reviewed by Houlston and Peto Introduction in this issue). For the reader’s reference, we have included a Over 200 hereditary cancer susceptibility syndromes comprehensive table of over 25 inherited cancer have been described, the majority of which are inherited syndromes (Table 1). From this longer list, we have in an autosomal dominant manner. Although many of chosen 10 syndromes that effectively underscore the these are rare syndromes, they are thought to account concepts of variable expression, pleiotropy, penetrance, for at least 5–10% of all cancer, amounting to a and heterogeneity of risk. They also highlight some substantial burden of morbidity and mortality in the of the exciting advances that have been made in our human population (Figure 1). While characterized by understanding of cell–cell interaction, intracellular their markedly increased risk of malignancy, these signalling, DNA replication and repair, and apoptosis. syndromes often predispose to benign tumours and generalized disease, as seen in Cowden syndrome (CS) and the multiple endocrine neoplasias. When the benign and malignant manifestations are considered together, Hereditary nonpolyposis colon cancer many of these syndromes show almost complete penetrance by age 70. In 1931, Aldred Warthin first reported on a family An inherited cancer susceptibility is suspected in with a hereditary pattern of stomach and endometrial families with the following characteristics: two or more cancer (Warthin, 1931). ‘Family G’ was further char- relatives with the same type of cancer on the same side acterized by Henry Lynch 40 years later (Lynch and of the family; several generations affected; earlier ages Krush, 1971), and subsequently, the autosomal domi- nant pattern of inheritance of gastrointestinal and *Correspondence: R Nagy, The Ohio State University Clinical Cancer gynaecologic cancers became known as hereditary Genetics Program, 2050 Kenny Road, 8th Floor Tower, Columbus, non-polyposis colon cancer (HNPCC, MIM 114500). OH 43221, USA; E-mail: [email protected] Many still prefer the term ‘Lynch syndrome’ to describe Review of 10 highly penetrant cancer syndromes R Nagy et al 6446 Women with HNPCC have a 9–12% lifetime risk of developing ovarian cancer (Aarnio et al., 1999b). Other cancers seen in HNPCC include small intestine, pan- creas, brain, hepatobiliary tract, and urinary tract, for which the lifetime risk is in the range of 2–4% (Aarnio et al., 1999a). Sebaceous gland tumours, multiple keratoacanthomas, basal cell carcinomas, and possibly breast cancer may be more common in the Muir-Torre variant (MIM 158320) of HNPCC. The Turcot variant (MIM 276300) should be considered when the family history includes glioblastoma mutiforme. Figure 1 While the majority of most common cancers are The colorectal cancer of HNPCC differs from sporadic, 5–10% are inherited and arise due to highly penetrant sporadic colorectal cancer in several ways. The average germline mutations. An additional 10–15% are referred to as age of onset is approximately 45 years, as compared to ‘familial’ and may be caused by the interaction of low-penetrance 63 years in the general population (Lynch et al., 1988). genes, gene–environment interactions, or both Typically, there is a paucity of adenomatous colonic polyps as compared to other familial polyposis condi- these families with colorectal, endometrial, and other tions. The proximal or ‘right’ colon is the preferred site extracolonic cancers. (60–70%) and there is significant risk for synchronous HNPCC is the most common form of hereditary and metachronous cancers. The progress from adenoma colorectal cancer, affecting as many as 1 in 400 to carcinoma also occurs more rapidly in HNPCC (2–3 individuals, and is caused by a germline mutation in years) than in sporadic tumours. Histologically, these any one of five DNA mismatch repair genes (MLH1, tumours are often poorly differentiated, with distinct MSH2, MSH6, PMS1,andPMS2). Molecular screen- mucoid and signet-cell features, and noted presence of ing of all Finnish patients with colorectal cancer has infiltrating lymphocytes. Despite this more rapid growth shown that at least 3% are attributable to germline pattern and the adverse histologic features seen on alterations in either MLH1 or MSH2 (Aaltonen et al., pathologic analysis, these lesions are associated with a 1998; Salovaara et al., 2000). The International Colla- better prognosis than sporadic colon tumours (Lynch borative Group on HNPCC established diagnostic and Smyrk, 1996; Sankila et al., 1996; Watson et al., criteria, known as the Amsterdam criteria, in 1991 1998). (Table 2) (Vasen et al., 1991). These criteria were further Characteristic errors of DNA replication known as modified in 1999 (Amsterdam II Criteria) in an attempt microsatellite instability (MSI) are the hallmark of to incorporate extracolonic cancers (Vasen et al., 1999). colorectal tumours in HNPCC. Microsatellites are short However, studies have shown that only 40–80% of repetitive stretches of DNA that occur throughout the families that meet the original criteria, and no more than genome, and occur in both coding and noncoding 50% meeting the modified criteria, have mutations in regions. In cells that are deficient in mismatch repair the associated mismatch repair genes (Bisgaard et al., (MMR), either as a result of a constitutional mutation 2002). For this reason, a third set of criteria, the in a DNA repair gene (e.g. MLH1 or MSH2 mutations Bethesda criteria, were developed. When compared to in HNPPC) or due to epigenetic silencing of such gene(s) the Amsterdam I and II criteria, the Bethesda criteria (e.g. MLH1 promoter methylation in sporadic colon are the most sensitive, especially in identifying HNPCC tumours), these repetitive stretches of DNA are prone families with pathogenic mutations (Syngal et al., 2000). to expansion or contraction (i.e. instability). When this However, the specificity of the Bethesda criteria is occurs within a coding microsatellite sequence, the significantly lower than that of its counterparts. It deletion or the addition of one or more nucleotides should be noted that the Bethesda criteria were recently can result in a frameshift mutation, that is, can disrupt revised (Umar et al., 2004), and the sensitivity and normal gene expression. The first example of this, as it specificity of the new criteria are not known. relates to HNPCC and colon cancer, was described in Penetrance in HNPCC is typically high and the 1995 when mutations in the transforming growth factor phenotype is quite variable within families. Males with beta receptor 2 (TGFBR2) gene were detected in eight HNPCC have virtually a 100% chance of developing MMR-deficient human colon cancer cell lines (Marko- colorectal cancer by age 70 (Aarnio et al., 1999b). witz et al., 1995). All of the mutations occurred in the Women appear to have a higher lifetime risk of same polyadenine tract (A)10 (also called BAT-RII), and endometrial cancer (42–60%) than colorectal cancer resulted in decreased expression of the type II receptor (54%) (Vasen et al., 1996; Aarnio et al., 1999b; Millar and dysregulation of the TGF-b/RII signalling pathway et al., 1999). However, for both men and women whose (see Figure 2). Since one of the major ligands for the first tumour is not treated with subtotal colectomy, the type II receptor, TGFb, is a key tumour suppressor in risk of developing a second primary colorectal cancer is colon cancer, this discovery provided a direct link 30% within 10 years after the original surgery, and 50% between DNA repair deficiency and dysregulation of within 15 years. The lifetime risk for stomach cancer is gene expression in colon epithelial cells. Since that time, 13–19%, although this may be much higher in families the presence of somatic frameshift mutations in coding of Asian descent (Aarnio et al., 1999b; Park et al., 2000). microsatellite repeats has been documented in both

Oncogene Review of 10 highly penetrant cancer syndromes R Nagy et al 6447 Table 1 Highly penetrant cancer syndromes Syndrome MIM#a Gene(s) Population incidence Penetranceb

Ataxia-telangiectasia 208900 ATM 1/30 000 to 1/100 000 100% Birt–Hogg–Dube 135150 BHD Unknown, rare Unknown, but reduced Bloom syndrome 210900 BLM Unknown, rare 100% Carney complex 160980 PRKRA1A Rare Unknown Cowden syndrome 158350 PTEN 1/200 000 90–95% Familial adenomatous polyposis 175100 APC 1/5000 to 1/10 000 B100% Familial malignant melanoma 155600 CDKN2A (TP16), Unknown B100% CMM1, CDK4 Familial paraganglioma 168000, SDHD, SDHB Rare Unknown syndrome 185470 Fanconi anaemia 227650 FANCA, FANCB, 1/360 000 100% FANCC, FANCD, FANCE, FANCF, FANCG, FANCL Hereditary breast–ovarian 113705, BRCA1 and BRCA2 1/500 to 1/1000 Up to 85% cancer syndrome 600185 Hereditary diffuse gastric 137215 CDH1 Unknown, rare 90% cancer Hereditary leiomyomatosis and 605839 FH Unknown, rare Unknown, but reduced renal cell carcinoma Hereditary nonpolyposis colon 114500 MLH1, MSH2, MSH6, 1 in 400 90% cancer PMS1, PMS2 Hereditary papillary renal cell 605074 MET Unknown Unknown, but reduced carcinoma Hyperparathyroidism–jaw 145001 HPRT2 Unknown, rare 90% tumour syndrome Juvenile polyposis syndrome 174900 MADH4 (SMAD4), 1/100 000 90–100% BMPR1A Li–Fraumeni syndrome 151623 TP53 Rare 90–95% Multiple endocrine neoplasia 131100 MEN1 1/100 000 95% type 1 Multiple endocrine neoplasia 171400, RET 1/30 000 70–100%c type 2 162300 Neurofibromatosis type 1 162200 NF1 1/3000 100% Neurofibromatosis type 2 101000 NF2 1/40 000 100% Nevoid basal cell carcinoma 109400 PTC 1/57 000 90% syndrome Nijmegen breakage syndrome 251260 NBS1 Rare 100% Peutz–Jeghers syndrome (PJS) 175200 LKB1 (STK11) 1/200 000 95–100% Retinoblastoma, hereditary 180200 RB 1/13 500 to 1/25 000 90% (RB) Rothmund–Thomson 268400 RECQL4 Rare 100% syndrome Tuberous sclerosis (TS) 191100, TSC1, TSC2 1/30 000 95–100% 191092 von Hippel–Lindau (VHL) 193300 VHL 1/36 000 90–95% Xeroderma pigmentosum 278700, XPA, ERCC3, XPC, 1/1 000 000d 100% 133510, ERCC2, XPE, ERCC4, 278720, ERCC5 278730, 278740, 278760, 278780

Syndromes shown in bold are covered in this review MIM numbers beginning with 1 indicate autosomal dominant; inheritance; those beginning with 2 indicate autosomal recessive inheritance those beginning with 6 are autosomal loci or phenotypes entered into the catalogue after May 1994. bPenetrance estimates are up until age 70 years, include both malignant and benign features and with the exception of MEN2, describe clinical penetrance. cThe clinical penetrance of MEN2A is 70% by age 70, but by biochemical testing (pentagastrin-stimulated calcitonin levels) is 95–100% by age 70. dIncidence of XP in Japan is 1/40 000 sporadic and hereditary tumours of various organs. For of the mutations identified in these studies occurred example, somatic frameshift PTEN mutations are found in one of two (A)6 repeats found in exons 7 and 8 of in approximately 15–20% of MSI-unstable colorectal the PTEN gene, suggesting that they are the direct result cancer, whether sporadic or HNPCC-associated (Zhou of MMR deficiency. Similar results have been shown for et al., 2002b), as well as a significant proportion of the RIZ (retinoblastoma protein interacting zinc-finger) HNPCC-associated endometrial cancers (Kuismanen gene in gastrointestinal tumours (Chadwick et al., 2000; et al., 2002; Zhou et al., 2002a). Of note, the majority Piao et al., 2000; Sakurada et al., 2001). RIZ also

Oncogene Review of 10 highly penetrant cancer syndromes R Nagy et al 6448 Table 2 Amsterdam I and II and Bethesda criteria Original Amsterdam criteria (Amsterdam criteria I) There should be at least three relatives with colon cancer and 1. One should be a first-degree relative of the other two 2. At least two successive generations should be affected 3. At least one should be diagnosed before age 50 4. Familial adenomatous polyposis should be excluded 5. Tumours should be verified by pathological examination

Revised Amsterdam criteria (Amsterdam criteria II) There should be at least three relatives with an HNPCC-associated cancer (cancer of the colorectum, endometrium, small bowel, ureter, or renal pelvis) and 1. One should be a first-degree relative to the other two 2. At least two successive generations should be affected 3. At least one should be diagnosed before age 50 4. Familial adenomatous polyposis should be excluded 5. Tumours should be verified by pathological examination

Bethesda guidelines (ver. 2004) Tumours from individuals should be tested for MSI in the following situations: 1. Colorectal cancer diagnosed in a patient who is less than 50 years of age 2. Presence of synchronous, metachronous colorectal, or other HNPCC-associated tumours, regardless of age 3. Colorectal cancer with the MSI-H histology diagnosed in a patient who is less than 60 years of age 4. Colorectal cancer diagnosed in one or more first-degree relatives with an HNPCC-related tumour, with one of the cancers being diagnosed under age 50 years 5. Colorectal cancer diagnosed in two or more first- or second-degree relatives with HNPCC-related tumours, regardless of age

into a tumour. Over 400 different pathogenic mutations have been registered in the international HNPCC database (http://www.nfdht.nl). Two genes, MLH1 and MSH2, account for the majority (90%) of all identified HNPCC alterations. Most of these are mutations that lead to a truncated protein, although upwards of 30% of MLH1 and 16% of MSH2 mutations are of the missense variety (Lynch and de la Chapelle, 2003). The MSH6 gene accounts for almost 10% of HNPCC families, with the majority having missense mutations (Kolodner et al., 1999). Cases of HNPCC caused by mutations in PMS2 and PMS1 are so few in number that genetic analysis has only been performed on a research basis to date. The fact that genomic rearrangements and mutations that affect control regions or the splicing apparatus may be missed by use of conventional methods alone, allelic separation, Southern hybridization and multiplex ligation-depen- Figure 2 TGFb–SMAD signalling pathways. Members of the dent probe amplification may be warranted, especially TGFb superfamily of receptors, such as TGFb receptors I and II or type 1 and 2 bone morphogenic protein receptors (BMPR1A and for families in which immunohistochemistry suggests a 2A) form receptor complexes after binding of their respective germline mutation but sequencing is negative (Wijnen ligands, TGFb and BMP. This leads to type 1 receptor-mediated et al., 1998; Gille et al., 2002; Nakagawa et al., 2002). Of phosphorylation of the SMADs, which transduce signal to the note, a recent study by Wagner et al. (2003) found nucleus after complexing with a co-SMAD, such as SMAD4. The genomic rearrangements accounting for 24% of all SMAD complex can then regulate transcription of a number of target genes through repression or activation. Adapted from mutations in a cohort of 59 clinically selected North Kretzchmar (2000) and Eng (2001b) American HNPCC families. Some studies have suggested that the lifetime risk of developing colorectal or endometrial cancer may be contains two coding poly(A) tracts, and one of its higher in MSH2 than in MLH1 families (Vasen et al., isoforms (RIZ1) has been implicated in cell cycle arrest 2001); other studies have failed to detect statistically and apoptosis (He et al., 1998; Jiang et al., 1999; Jiang significant differences (Parc et al., 2003). However, and Huang, 2000). reports do substantiate that endometrial cancer may be As mentioned above, germline mutations in specific more common in families with germline MSH6 altera- DNA mismatch repair genes (MLH1, MSH2, MSH6, tions as compared to the other mismatch repair genes. PMS1, and PMS2) cause HNPCC. Affected patients In particular, study of a large Dutch family with an generally have inactivation of one copy, with subsequent MSH6 alteration not only showed reduced penetrance somatic loss of the wild-type allele in cells that develop of colorectal cancer (only 32% by age 80) but

Oncogene Review of 10 highly penetrant cancer syndromes R Nagy et al 6449 endometrial cancer was the most common tumour type Gardner’s syndrome (Gardner and Richards, 1953), among carrier females (Wagner et al., 2001). Both which we now know is allelic to FAP. The extracolonic colorectal and endometrial cancers in this family features of FAP include congenital hypertrophy of the occurred at later ages of onset than expected in HNPCC retinal pigment epithelium (CHRPE), which is found in (Wagner et al., 2001). Wijnen et al. (1999) also noted a 60–88% of affected individuals. These discrete, flat, lower tumour frequency, delayed age of cancer onset, pigmented lesions do not affect vision and are usually and incomplete penetrance in MSH6 mutation carriers bilateral or multifocal in FAP, as compared to the in their study cohort. In the Muir-Torre variant of isolated or unilateral lesions seen in the general HNPCC, the vast majority of germline mutations population (Burn et al., 1991; Soloman and Burt, identified have been in MSH2, with a few families 2004). Dental anomalies (unerupted teeth, congenital harbouring MLH1 alterations. One-third of patients absence of one or more teeth, supernumerary teeth, with Turcot’s syndrome have mutations in MSH2. dentigenous cysts, and odontomas), epidermoid cysts In certain populations, founder mutations in MLH1 (notably on the scalp), and osteomas of the mandible and MSH2 have been identified. In the Finnish (90%), skull, fingers, toes, and long bones occur more population, for example, two mutations in MLH1 (a often in individuals with FAP. Mesenteric fibrosis may 3.5 kb genomic deletion in exon 16; a splice-acceptor site occur after surgery or pregnancy, but can also occur mutation of exon 6) account for 63% of all disease- spontaneously. Soft-tissue desmoid tumours typically causing mutations in families with HNPCC (Nystrom- develop in the abdominal cavity but can occur anywhere Lahti et al., 1995). The MLH1 W714X mutation in the body. Desmoid tumours occur in approximately appears to have a founder effect in the Swiss (Hutter 5–10% of children and adults with FAP (Bertario et al., et al., 1996). A 1.8 kb deletion involving exon 11 of 2001). Lastly, polyps of the upper gastrointestinal tract, MLH1 may represent a founding mutation in HNPCC including the gastric fundic glands, antrum, and families originating in southern China (Chan et al., duodenum, can also be present (Bulow et al., 1995). 2001). The MSH2 1906G4C mutation is highly Individuals with FAP can also develop extracolonic penetrant and accounts for approximately one-third of malignancies. While gastric adenomas and fundic gland Ashkenazi Jewish families that meet the Amsterdam polyps are common, affecting 10 and 50% of patients, criteria (Foulkes et al., 2002). Of note, recent studies respectively, the associated risk for cancer is small identified a deletion of exons 1–6 in MSH2 in nine (Bulow et al., 1995). There is more concern for the distantly related North American families (Wagner et al., adenomas that invariably form in the second and third 2002; Lynch et al., 2004). Genealogic, molecular, and portions of the duodenum (97%), especially in the haplotype studies show that this deletion represents a periampullary region, as these present an increased risk common founder mutation that can be traced back to an (4–12%) for malignancy (Bulow et al., 1995; Heiskanen 18th century German family (Wagner et al., 2002, 2003; et al., 1999; Kadmon et al., 2001). Papillary thyroid Lynch et al., 2004). carcinoma occurs in approximately 2% of individuals with FAP, most often in female carriers, and at an average age of 28 years (Cetta et al., 2000). Other Familial adenomatous polyposis cancers observed in FAP include hepatoblastoma in children (risk of 1.6% to age 6 years), pancreatic Familial adenomatous polyposis (FAP, MIM 175100), carcinoma (approximately 2% lifetime risk), and CNS which accounts for approximately 1% of hereditary tumours in the Turcot variant (MIM 276300) (Giardiel- colorectal cancer, is characterized by the development of lo et al., 1993, 1996). hundreds to thousands of adenomatous polyps through- There is a mild clinical variant of FAP known as out the colon and rectum, with an extremely high attenuated FAP (AFAP), which is characterized by lifetime risk of colon cancer. It is an autosomal fewer polyps (between 10 and 100, with an average of dominant condition caused by germline mutations in 30) and a later age of colon cancer diagnosis (50–55 the adenomatous polyposis coli (APC) gene and affects years). The adenomas in AFAP tend to aggregate more about 1 in every 5000–10 000 people (Burn et al., 1991; often in the proximal colon, although they can be Jarvinen, 1992). Most individuals (75–80%) will have an present anywhere in the colon and in the upper affected parent, while the remainder are the result of a gastrointestinal tract. The lifetime risk for colon cancer new mutation. While penetrance is almost complete, in AFAP is also high, although evidence suggests that there is significant variability within and between desmoid tumours and CHRPE are rare or absent in families. AFAP (Burn et al., 1991). The clinical diagnosis of FAP is made if an individual The gene for FAP was first mapped to chromosome 5 has greater than 100 colorectal adenomas. In all, 75% of in 1987 (Bodmer et al., 1987), and identified as the APC individuals will develop polyps by age 20, and nearly gene in 1991 (Groden et al., 1991; Kinzler et al., 1991; 90% by age 30. Although the polyps are benign initially, Nishisho et al., 1991). The gene contains 15 exons, with at least a subset will proceed to malignancy. The average the last exon comprising more than 75% of the coding age of colorectal cancer diagnosis is 39 years; 90% of sequence. Biallelic somatic APC mutations are found in untreated patients will have malignancy by age 50 the very earliest stages of the adenoma–carcinoma (Bussey, 1975). Historically, the presence of both colonic sequence in colonic epithelial cells, supporting its role and extracolonic features has been referred to as in tumour initiation. The normal protein product is a

Oncogene Review of 10 highly penetrant cancer syndromes R Nagy et al 6450 tumour suppressor that has a multitude of important MYH is a base-excision repair gene, whose protein functions in the cell, including cell cycle control, product is responsible for the removal of adenines from differentiation, migration, and apoptosis. The role of mispairs with 8-oxoguanine that arise during replica- APC in many of these processes occurs through its tion. Al-Tassan et al. (2002) first described a British interactions with b-catenin in the Wnt signalling path- Caucasian family with three siblings with colorectal way. APC binds to b-catenin and targets it for cancer and each was found to be a compound degradation by the cell. This, in turn, prevents b-catenin heterozygote for the MYH missense variants Y165C from entering the nucleus and participating in the Tcf- and G382D. Follow-up study of seven additional mediated transcription of a number of target genes, unrelated patients with greater than 100 adenomas including MYC (Rubinfeld et al., 1993; Korinek et al., identified three individuals of British Caucasian descent 1997; Chung, 2000; Goss and Groden, 2000). More either homozygous for the Y165C mutation or com- recently, studies in mice heterozygous for Apc mutations pound heterozygotes (Y165C/G382D) (Jones et al., show a role for APC in kinetochore–microtubule 2002). Another three were homozygous for the exon attachment and chromosome segregation at mitosis 14 nonsense mutation E466X and were of Indian (Kaplan et al., 2001). Furthermore, Fodde et al. (2001) descent. The tumours of these carriers all exhibited an showed that APC, which forms a complex with EB1 excess of somatic G : C4T : A transversions when proteins, is critical for the stabilization of microtubule– compared to sporadic tumours, as would be expected kinetochore interactions. Thus, inactivation of APC given MYH’s role in base-excision repair (Jones et al., may contribute to chromosomal instability (CIN) and 2002). A larger series of 152 patients with multiple an enhanced mutation rate, promoting tumour growth adenomas (3–100), and 107 patients with polyposis coli in colorectal cancer (Fodde et al., 2001). and without germline APC mutation was then screened Over 500 germline mutations have been described for germline mutations; approximately one-third of (http://archive.uwcm.ac.uk/uwcm/mg/search/119682.html). those with 15–100 adenomas had biallelic germline Truncating mutations between codons 169 and 1393 MYH mutation (Sieber et al., 2003). For those with result in the classic FAP phenotype. The two most com- classic polyposis, 7.5% had disease due to MYH.More mon germline mutations, 5 bp deletions in codons 1061 recently, the two common MYH mutations were and 1309, occur in the mutation cluster region of exon examined in a population-based series of Finnish 15, and correlate with a high number of adenomas at colorectal cancer patients and showed that only 0.4% an early age (Soravia et al., 1998; Wallis et al., 1999; (4/1042) were homozygous (Enholm et al., 2003). Friedl et al., 2001). Retinal lesions are commonly Although the mutation frequency in CRC patients was associated with alterations between codons 463 and 1387 small, it reached statistical significance when compared (Olschwang et al., 1993; Moisio et al., 2002). Desmoid to the frequency in Finnish controls (0/424). Of those tumours and mandibular osteomas, as seen in the who were homozygous, the average age at onset of colon Gardner variant, occur with mutations between codons cancer was 55 (range 40–66 years) and all four 1403 and 1578 (Wallis et al., 1999; Moisio et al., 2002). individuals had multiple polyps, ranging from only 5 In contrast, the attenuated FAP phenotype results from in one patient to 50–100 in another. This study mutations either in the 50 part of the APC gene (50 to underscores the importance of clinical history and also codon 158), the alternatively spliced exon 9, or in the far cautions against widespread population testing for 30 part of the gene beyond codon 1595 (Spirio et al., 1993; MYH mutations. van der Luijt et al., 1995; Friedl et al., 1996; Walon et al., To further clarify the role that MYH and base- 1997; Soravia et al., 1998; Moisio et al., 2002). A mutation excision repair might play in bowel neoplasia, Lipton discovered at codon 1307 of the APC gene generates a et al. (2003) determined the genetic pathway in 130 hypermutable polyadenine tract among the Ashkenazim colorectal adenomas and 19 carcinomas from 22 (Laken et al., 1997). This I1307K variant is found in 6% of patients with MYH-associated polyposis (MAP). They Ashkenazi Jews in the general population, and 10% of concluded that the MAP pathway of carcinogenesis those with colon cancer (Laken et al., 1997). It confers a differed from both the CIN and MSI pathways, while twofold increased risk for colon cancer, but does not cause sharing elements of both. MAP tumours showed a high significant polyposis. frequency of APC mutation (21% of adenomas and 43% of cancers), but no evidence of b-catenin mutation. Interestingly, all of the APC protein-truncating muta- tions were G4T transversions. Similarly, the same MYH gene and autosomal recessive heritable colorectal G4T mutation (G12C) in the KRAS gene was found cancer in 9 of 14 (64%) of cancers and 13 of 30 (43%) of adenomas, suggesting other targets of genetic instability For patients with polyposis coli who test negative for a in these tumours. Most MAP cancers were near diploid mutation in APC, or for those with a more attenuated (CIN-), showed no microsatellite instability, and had phenotype (between 15 and 100 colorectal adenomas) low frequencies of loss of heterozygosity (LOH). and a family history compatible with autosomal Clearly, further studies are needed to extrapolate recessive inheritance, recent studies have found that these findings, but early results imply that highly biallelic alterations in the MYH gene may be the cause penetrant recessive susceptibility genes such as MYH (Sieber et al., 2003). may very well account for a significant proportion of

Oncogene Review of 10 highly penetrant cancer syndromes R Nagy et al 6451 hereditary colon neoplasia. The fact that two MYH Histopathology plays a critical role in the diagnosis of variants (Y165C and G382D) comprise 86% of the JPS (Helwig, 1946). The typical JPS polyp is unilobu- mutations in white European patients, while all patients lated and pedunculated, spherical in shape with a identified of Indian descent (n ¼ 4) have the E466X smooth outer surface. In contrast to other hamartoma- variant, implies that founder mutations may confer tous polyps, these lack a smooth muscle core but instead susceptibility in various ethnic populations (Marra and show an internal dense inflammatory response, with Jiricny, 2003; Sampson et al., 2003; Sieber et al., 2003). predominant mesenchymal stroma that entraps normal Data so far suggest that the heterozygous state alone epithelial cells, often forming dilated cysts (Jass et al., may not increase risk, although larger well-controlled 1988). Less typical (20%) are JPS polyps that are population-based series are needed. Interestingly, an multilobulated, with each lobe separated by well-defined initial study of unselected sporadic colorectal tumours clefts (Jass et al., 1988). did not find somatic MYH mutation or absence of Congenital anomalies have been reported in 11–20% mRNA and protein; this suggests that MYH loss may be of individuals with JPS, more often in sporadic cases rarely involved in the pathogenesis of sporadic bowel (Coburn et al., 1995). These can involve the gastro- cancer (Halford et al., 2003). intestinal tract (including malrotation of the gut), heart, central nervous system, and genitourinary system (Desai et al., 1998; Guillem et al., 1999). Clubbing of the Juvenile polyposis fingertips is common, macrocephaly and hypertelorism less so, and cleft lip/palate is infrequently seen. Juvenile polyposis (JPS, MIM 174900) is a rare Juvenile polyposis is caused by mutations in at least autosomal dominant hamartoma syndrome character- two genes. Germline mutations in MADH4 (also known ized by the development of multiple juvenile polyps as SMAD4, DPC4) encoding SMAD4 account for throughout the gastrointestinal tract, congenital anoma- 15–30% of familial and sporadic cases (Howe et al., lies, and an increased risk for malignancy (McColl et al., 1998). Mutations in the bone morphogenic protein 1964; Jarvinen and Franssila, 1984). It has almost receptor 1A gene (BMPR1A) may account for an complete penetrance, with two-thirds of individuals additional 20–40%, especially those families originating manifesting clinical features by early adulthood. Ap- from Europe (Howe et al., 2001; Zhou et al., 2001a; proximately half of all cases have no family history Sayed et al., 2002). Both MADH4 and BMPR1A belong (Coburn et al., 1995). JPS is caused by mutations in at to the TGFb superfamily. BMPR1A is phosphorylated least two different genes, MADH4 and BMPR1A. The by, and dimerizes with, a specific type II BMP receptor. clinical diagnosis is made if an individual meets any of In turn, this activated complex signals through the the criteria as outlined in Table 3 (Jass et al., 1988). intracellular SMAD1 or related SMAD5 and SMAD8 Juvenile polyps occur in 1–2% of the general proteins, increasing their affinity for SMAD4, and population, with most found in children and adolescents gaining access to the nucleus for the transcriptional (Helwig, 1946; Toccalino et al., 1973). These are often regulation of downstream target genes (see Figure 2) solitary juvenile polyps, and as such are not associated (Massague, 2000; Eng, 2001b). with an increased risk for malignancy. The average age To date, the only genotype–phenotype correlation of diagnosis of solitary juvenile polyps is 3–5 years observed in JPS is the marked prevalence of gastric (Horrielleno et al., 1957; Roth and Helwig, 1963; polyps in individuals with MADH4 mutations as Toccalino et al., 1973). In contrast, the frequency of compared to those with germline BMPR1A alterations JPS is suggested to be 1 in 100 000 individuals. The mean (Friedl et al., 2002). It is likely that there is at least one age of diagnosis is 16 years (Coburn et al., 1995; Sayed other JPS gene that has not been identified yet. While et al., 2002); however, some cases present in infancy and other members of the TGFb–SMAD superfamily would others much later in life, even in the seventh decade be ideal candidates, no germline mutations in the genes (Burt et al., 1993). Polyp number varies between encoding SMAD1, SMAD2, SMAD3, and SMAD5 individuals, even in the same family, but can be have been identified to date (Bevan et al., 1999). anywhere from 5 to 200 (Desai et al., 1994). They are It is known that MADH4 acts as a tumour suppressor most often found in the lower bowel (98%) but can also gene in tumours of the pancreas. However, the exact develop in the stomach (15%) and small intestine (7%) mechanism(s) for tumour formation in the gastrointest- (Desai et al., 1994). There is also an increased lifetime inal tract for both MADH4 and BMPR1A remains open risk for malignancy of 10–60% for gastrointestinal for debate. Woodford-Richens et al. (2000) performed (colorectal, gastric, and duodenal) and pancreatic cancer fluorescence in situ hybridization studies to demonstrate (Jarvinen and Franssila, 1984; Jass et al., 1988). that biallelic inactivation of MADH4 occurs in the trapped epithelial layers and stromal cells of JPS polyps. This suggests that malignant progression occurs through the epithelial component of the hamartomatous polyp. Table 3 Clinical diagnostic criteria for Juvenile polyposis syndrome Less is known of the role of BMPR1A in tumour 1 More than five juvenile polyps of the colorectum initiation. Initial studies by Jacoby et al. (1997) showed 2 Juvenile polyps throughout the gastrointestinal tract that LOH on chromosome 10q22–23 occurred predo- 3 Any number of juvenile polyps with a family history of juvenile polyposis minantly in the lamina propria rather than the epithelial cells of juvenile polyps. This might suggest that a

Oncogene Review of 10 highly penetrant cancer syndromes R Nagy et al 6452 ‘landscaper’ effect results in an abnormal stromal The risk of malignancy in PJS is 10- to 18-fold microenvironment leading to epithelial dysplasia and increased over the general population, and these tumour formation in some forms of JPS. malignancies often occur at a relatively young age (Giardiello et al., 1987; Boardman et al., 1998). The most common locations are the colon, small intestine, Peutz–Jeghers syndrome and stomach (Giardello et al., 1987). Additionally, pancreatic carcinoma, breast carcinoma, Sertoli cell Peutz–Jeghers syndrome (PJS, MIM 175200) is another tumours of the testis in prepubescent males, and sex rare hamartomatous polyposis condition, affecting cord tumours with annular tubules (SCTAT) of the approximately 1 in 200 000 people. It is autosomal ovary or adenoma malignum (multicystic adenocarci- dominant with nearly complete penetrance (Hemminki noma) of the uterine cervix in females, occur with et al., 1997). The original description is credited to Peutz increased frequency (Cantu et al., 1980; Young et al., in 1921 (Peutz, 1921), followed by Jegher’s review in 1982). 1949 of 10 families with gastrointestinal polyposis and Germline mutations in LKB1 (STK11), on 19p13.3, mucocutaneous pigmentation, with illustration of the encoding a multifunctional serine/threonine kinase, were risk for invasive carcinoma (Jeghers et al., 1949). The found in a proportion of PJS individuals and kindreds in most common location of PJS polyps is the small bowel, 1998 (Hemminki et al., 1997, 1998; Olschwang et al., specifically the upper jejunum (78%). However, these 1998). LKB1 mutations have been found in only 50% of hamartomatous polyps can occur anywhere along the cases, leading to the suggestion of locus heterogeneity. gastrointestinal tract. Rarely, they are seen within the LKB1 has nine exons, and the normal protein product oesophagus, nasopharynx, and urinary tract. The main acts as a tumour suppressor, a notable role for a protein complication is intussusception, which can result in kinase. Studies show that biallelic inactivation of LKB1, intestinal obstruction, bleeding, and anaemia. These are either through germline mutation plus somatic muta- the usual presenting signs and symptoms and occur tion, or more commonly promoter hypermethylation of most often in the mid- to late teenage years, but may the wild-type allele, causes hamartomatous polyps to even occur in infancy. Approximately one-half of cases develop (Gruber et al., 1998; Miyaki et al., 2000; Entius are due to germline mutation in the LKB1 gene. A et al., 2001). Given that adenomatous changes occur clinical diagnosis of PJS is made if an individual meets in these polyps, and the associated gastrointestinal any of the criteria as outlined in Table 4 (Aaltonen et al., tumours are adenocarcinomas, analysis of the genes 2000). involved in the adenoma–carcinoma sequence has been As with JPS, histopathology is critical in making the performed. This has revealed somatic mutation of the diagnosis of PJS, as the PJS polyp has a diagnostically b-catenin gene and TP53 gene, but not of the APC gene, useful central core of smooth muscle that extends, in a in PJS polyps (Miyaki et al., 2000). However, somatic tree-like manner (‘arborization’), into the superficial APC mutation was seen in four of five PJS-associated epithelial layer (reviewed by Aaltonen et al., 2000). carcinomas studied by Entius et al. (2001), indicative of Invagination of the epithelial layer occurs, essentially some role for APC in the later stages of carcinogenesis. trapping these cells within the smooth muscle compo- KRAS mutation was a rare event in either hamartoma nent, and causing ‘pseudo-invasion’ of the bowel wall or carcinoma (Gruber et al., 1998). In all, these results that can be misdiagnosed as cancer (Shepard et al., suggest that the abnormal growth of the PJS polyp 1987). This involvement of the three tissue layers leads to additional somatic mutation, such as in the predisposes to intussusception and the formation of b-catenin gene, resulting in a change from hamartoma the distinctive lobulated PJS polyp. to adenoma, with continued progression to malignancy Cutaneous melanin deposition is the other cardinal via alternative pathways from most sporadic carci- feature of PJS. This most often occurs in the perioral nomas (Esteller et al., 2000; Miyaki et al., 2000; Entius region or buccal mucosa but can also be seen on the et al., 2001). The observation that LKB1 mutation genitalia, anus, hands, or feet. Although the pigmenta- and LOH of markers in the 19p region are infrequent tion usually appears in infancy and fades at puberty, in randomly selected sporadic colorectal tumours pigmented spots have been reported to appear as late as lends further evidence to this theory (Avizienyte et al., age 70. Similar skin pigmentation can be seen in other 1998; Gruber et al., 1998; Miyaki et al., 2000; Entius hereditary conditions such as the Laugier–Hunziker et al., 2001). syndrome, Carney complex, and LEOPARD syndrome, LKB1 is widely expressed in many tissues (Hemminki but the associated intestinal polyposis is not seen in et al., 1998) and one of its major roles may be as an these conditions (Veraldi et al., 1991; Chrousos and inducer of apoptosis. Recent work by Karuman et al. Stratakis, 1998). (2001) showed that LKB1 is upregulated in normal mucosa, while in the intestinal polyps of PJS there is a Table 4 Clinical diagnostic criteria for Peutz–Jeghers syndrome noticeable reduction in the number of apoptotic cells. 1 Three or more histologically confirmed PJS polyps p53 and LKB1 were also found to interact functionally 2 Any number of PJS polyps or characteristic mucocutaneous such that overexpression of LKB1 induces apoptosis pigmentation, with a positive family history of PJS only in cells with wild-type TP53 (Karuman et al., 2001). 3 Any number of PJS polyps with characteristic mucocutaneous In the epithelial cells of the small intestine, LKB1 is pigmentation normally expressed in the nucleus and cytoplasm

Oncogene Review of 10 highly penetrant cancer syndromes R Nagy et al 6453 (Karuman et al., 2001). Transfection of mouse Lkb1 Hereditary breast ovarian cancer cDNAs into COS cells demonstrates that endogenous expression occurs predominantly in the nucleus Hereditary breast ovarian cancer (HBOC, MIM 113705) although LKB1 also functionally interacts with LIP1, syndrome is the most common form of inherited breast a cytoplasmic-based protein in mammalian cells (Smith cancer and is caused by germline mutations in BRCA1 et al., 2001). When coexpressed, LIP1 becomes the on 17q11 and BRCA2 on 13q12–q13 (Miki et al., 1994; cytoplasmic anchor for LKB1, thus regulating its Wooster et al., 1995). The prevalence of BRCA subcellular localization and allowing for phosphoryla- mutations in the general population is estimated to be tion of cytoplasmic as well as nuclear substrates (Smith between 1 in 500 and 1 in 1000 (Claus et al., 1991; Ford et al., 2001). In this fashion, LKB1 might induce et al., 1995), although this is much higher in certain apoptosis following redistribution to the cytoplasm, founder populations, such as the Ashkenazi Jewish and with subsequent phosphorylation of p53 or other Icelandic populations (see Table 5) (Roa et al., 1996; apoptotic pathway regulators. In that LKB1 has been Struewing et al., 1997). The proportion of HBOC shown to translocate to the mitochondria in the attributable to BRCA1/2 mutations is poorly defined presence of p53 (Karuman et al., 2001), and many types and estimates depend upon the population studied, the of signals converge upon the mitochondria to initiate number of breast and ovarian cancer cases in the family, apoptosis (Gross et al., 1999), this remains a possibility. and the mutation detection technique utilized. In Even more intriguing is the evidence that LIP1 co- families with X2 cases of breast cancer (o50 years) precipitates SMAD4. Together with LKB1, they form a and at least one case of ovarian cancer, 490% will carry ternary complex, which, as such, implies a role in a deleterious mutation. In families with site-specific regulating TGFb–SMAD superfamily signalling (Smith breast cancer, these figures are lower and range from 30 et al., 2001). In point of fact, LIP1 may very well be the to 81% (Ford et al., 1998). In addition, a significant missing link that could explain some similar phenotypic proportion of young breast cancer cases unselected for features of PJS and JPS. family history will carry a BRCA1 or BRCA2 mutation. LKB1 was recently found to be the major upstream This proportion is as high as 20% in women of kinase of AMP-activated protein kinase (AMPK), Ashkenazi Jewish ancestry diagnosed before the age of which is part of a protein kinase cascade that plays a 40 (Neuhausen et al., 1996; Offit et al., 1996). pivotal role in energy homeostasis (Woods et al., 2003). Along with early-onset breast and ovarian cancer, How phosphorylation (or lack thereof) of AMPK other cancers seen more commonly in BRCA mutation relates to the phenotype of PJS in unclear, but recent carriers include fallopian tube cancer, pancreatic cancer, evidence has shown that the b1-subunit of AMPK may stomach cancer, and laryngeal cancer (Consortium, act as a p53-independent stress-responsive protein that 1999; Brose et al., 2002). The lifetime relative risk of inhibits tumour growth and that AMPK may be linked these cancers is on the order of two- to fourfold, with the to cellular senescence. Furthermore, tuberin, encoded by exception of fallopian tube cancer (RR ¼ 120) (Brose TSC2, which is one of the susceptibility genes for et al., 2002). Male BRCA mutation carriers have an tuberous sclerosis complex, is downstream of AMPK increased risk of developing prostate cancer (16% risk (Inoki et al., 2003). Interestingly, activated Akt down- by age 70) and male breast cancer (5–10% lifetime risk regulates tuberin (Manning et al., 2002) and, theoreti- in BRCA2 carriers) (Struewing et al., 1997). Identifica- cally, dysregulated PTEN can activate Akt, which tion of high-risk individuals and families can lead to should in turn downregulate tuberin signalling. This earlier and increased cancer surveillance, particularly interplay of signalling pathways may begin to explain for breast and ovarian cancer, and the option of chemo- some of the common phenotypic features, for example, prevention and/or prophylactic surgery to reduce hamartomatous gastrointestinal polyps, shared by cancer risk. CS/Bannayan–Riley–Ruvalcaba syndrome (BRRS) Penetrance estimates for BRCA1 and BRCA2 vary (see below), PJS, and tuberous sclerosis complex. widely depending on the population studied, and are

Table 5 Founder mutations in BRCA1 and BRCA2 Population Mutations in BRCA1 Mutations in BRCA2 References

African-American M1775R, 1832del5, 5296del4 Gao et al. (1997) Ashkenazi-Jewish 185delAG, 5382insC 6174delT Neuhausen et al. (1996), Struewing et al. (1995), and Tonin et al. (1996) Dutch 2904delAA, del510, del3835 5573insA Peelen et al. (1997) and Petrij-Bosch et al. (1997) French-Canadian C4446T 8765delAG Simard et al. (1994) and Tonin et al. (1999) English 4184del4 2157delG Evans et al. (2004) Icelandic 999del5 Thorlacius et al. (1996) Norwegian 1675delA, 1135insA Andersen et al. (1996) Polish 5382insC, C61G, 4153delA Gorski et al. (2000) Russian 5382insC, 4153delA Gayther et al. (1997a) Scottish 2800delAA Liede et al. (2000) Swedish Q563X, 3166ins5, 1201del1, 4486delG Ha˚ kansson et al. (1997) and Johannsson et al. (1996) 2594delC

Oncogene Review of 10 highly penetrant cancer syndromes R Nagy et al 6454 generally higher in studies of multiple-case families are missense mutations. Some of these are deleterious (Easton et al., 1993; Ford et al., 1998) as compared to and others are classified as variants of uncertain those based on unselected series of patients (Thorlacius significance. Evidence for genotype–phenotype correla- et al., 1998; Hopper et al., 1999). This wide range in risk tions exists. Mutations in and around exon 11 of is most likely due to several factors including allelic risk BRCA2, which is often referred to as the ovarian cancer heterogeneity (i.e. different mutations causing different cluster region (OCCR), confer a higher ovarian cancer cancer risks) as well as modifying influences, both risk and lower breast cancer than mutations in other genetic and environmental. Based on studies of multiple- areas of the gene (Gayther et al., 1997b; Thompson case families presenting to high-risk clinics, the risk of et al., 2001). BRCA1 mutations that lie 30 of nucleotides developing female breast cancer in BRCA1 and BRCA2 4200–4400 confer a lower ovarian cancer risk than mutation carriers is between 70 and 85% by age 70. The mutations 50 of this region (Gayther et al., 1995). Lastly, risk of ovarian cancer differs slightly between BRCA1 BRCA1 mutations in and around exon 11 confer a lower and BRCA2 carriers, with BRCA1 carriers having a risk of breast cancer than mutations in the 50 and 30 44–63% lifetime risk and BRCA2 carriers a 27–31% regions of the gene (Thompson and Easton, 2002). lifetime risk (Easton et al., 1993; Struewing et al., 1997). Recently, cumulative risks for breast and ovarian cancer were estimated by pooling pedigree data from 22 studies Cowden syndrome of 8139 index cases unselected for family history (Antoniou et al., 2003). BRCA1 mutation carriers had CS (MIM 158350) is an autosomal dominant disorder a cumulative risk of developing breast or ovarian cancer and part of the PTEN hamartoma tumour syndrome by age 70 of 65 and 39%, respectively. For BRCA2 (PHTS), which also includes Bannayan-Riley-Ruvalcaba mutation carriers, the risks were 45% for breast cancer Syndrome (BRRS), Proteus syndrome, and Proteus-like and 11% for ovarian cancer (Antoniou et al., 2003). The syndrome (Zhou et al., 2001b; Waite and Eng, 2002). authors concluded that both mutation status and family Before the identification of the gene for CS, incidence history should be taken into account when counselling estimates were on the order of 1/1 000 000 (Nelen et al., high-risk families. 1996). However, since that time, the gene for CS has BRCA1, identified in 1994 by positional cloning been identified (see below) and molecular-based esti- methods, encodes a 1863-amino-acid polypeptide (Miki mates of the incidence are B1/200 000 (Nelen et al., et al., 1994). The N-terminus contains a zinc-finger 1997, 1999). Because many of the features of CS are domain that interacts both directly and indirectly with common in the general population (e.g. fibrocystic breast DNA (Miki et al., 1994). Exon 11 of BRCA1 encodes disease, uterine fibroids), this condition is underdiag- over 60% of the protein, contains two nuclear localiza- nosed and therefore the incidence may be even higher. tion signals, and interacts with RAD-51 (Scully et al., The most commonly reported manifestations of CS 1997b), p53 (Zhang et al., 1998), RB (Aprelikova et al., include mucocutaneous lesions (90–100%), fibrocystic 1999) and c-Myc (Wang et al., 1998). The C-terminus breast disease (76% of affected females), thyroid contains a transcription activation domain and interacts abnormalities (50–67%), multiple uterine leiomyoma, with RNA polymerase II (Scully et al., 1997a) and gastrointestinal polyps (usually hamartomas, 40%), and BRCA2 (Chen et al., 1998), as well as other proteins. macrocephaly (38%). Trichilemmomas and papilloma- BRCA1 has been shown to play a role in a multitude of tous papules are considered pathognomonic for the cellular processes, including but not limited to DNA disease (Eng, 1997, 2000b). Affected individuals also transcription, cell cycle regulation, DNA damage repair, have an increased risk for several malignancies, includ- and apoptosis (Somasundaram, 2003). It is thought to ing breast cancer (25–50% lifetime risk), thyroid cancer, act as a tumour suppressor, which is supported by the typically follicular-type (3–10% lifetime risk), and fact that many BRCA1-associated tumours show LOH endometrial cancer (lifetime risk unknown) (Starink of the wild-type allele (Smith et al., 1992; Cornelis et al., et al., 1986; Longy and Lacombe, 1996; Marsh et al., 1995). 1998b; Eng, 1997, 2000b) By age 30, B99% of affected The BRCA2 protein has also been implicated in DNA individuals will have developed at least the mucocuta- repair and has recently been shown to regulate the neous signs of CS. Consensus diagnostic criteria for CS activity of RAD-51, which is required for homologous were developed in 1996 by the International Cowden recombination leading to double-stranded DNA repair Consortium (ICC) and have recently been revised (Jasin, 2002). Interestingly, biallelic inactivating muta- (Table 6) (Eng, 2000b). tions in BRCA2 were recently identified in patients with The CS susceptibility locus was mapped to 10q22–q23 Fanconi anaemia, group D1 (FANC-D1) (Howlett et al., (Nelen et al., 1996). Subsequently, germline mutations in 2002), linking two seemingly unrelated syndromes to a PTEN, localized to 10q23.3, were found in CS (Liaw common DNA damage response pathway. et al., 1997). PTEN, comprising nine exons, encodes a To date, over 750 different mutations in BRCA1 and 403-amino–acid, almost ubiquitously expressed, dual- 400 in BRCA2 have been identified (http://research.nh- specificity phosphatase with lipid and protein phospha- gri.nih.gov/bic/). The majority of these are frameshift or tase activities (Li and Sun, 1997; Li et al., 1997; Steck nonsense mutations that lead to premature truncation et al., 1997; Weng et al., 2001a, 2002). PTEN is the and loss of function, consistent with the tumour major lipid phosphatase that signals down the phos- suppressor model. Less than 10% of BRCA mutations phoinositol-3-kinase (PI3K)/Akt pathway resulting in

Oncogene Review of 10 highly penetrant cancer syndromes R Nagy et al 6455 Table 6 International Cowden Syndrome Consortium operational criteria for the diagnosis of Cowden syndrome (ver. 2000) Pathognomonic criteria (mucocutanous lesions): Trichilemmomas, facial Acral keratoses Papillomatous papules Mucosal lesions

Major criteria Breast carcinoma Thyroid carcinoma (nonmedullary), especially follicular thyroid carcinoma Macrocephaly (megalencephaly, e.g. X97%ile) Lhermitte–Duclos disease (LDD) Endometrial carcinoma

Minor criteria Other thyroid lesions (e.g. adenoma or multinodular goiter) Mental retardation (e.g. IQ p75) Gastrointestinal hamartomas Fibrocystic disease of the breast Lipomas Fibromas GU tumours (e.g. renal cell carcinoma or uterine fibroids) or malformation

Operational diagnosis in an individual: 1. Mucocutanous lesions alone if (a) there are six or more facial papules, of which three or more must be trichilemmoma; (b) cutaneous facial papules and oral mucosal papillomatosis; (c) oral mucosal papillomatosis and acral keratoses; (d) palmoplantar keratoses, six or more 2. Two major criteria, of which one must include macrocephaly or LDD 3. One major and three minor criteria 4. Four minor criteria

Operational diagnosis in a family where one individual is diagnostic for Cowden 1. One or more pathognomonic criterion/ia 2. Any one major criterion with or without minor criteria 3. Two minor criteria

Operational diagnostic criteria are reviewed and revised on a continuous basis as new clinical information becomes available. The 1995 and 2000 versions have been accepted by the US-based NCCN High Risk/Genetics Panel

0 G1 cell cycle arrest and/or apoptosis, depending on the and 5 of it, as well as missense mutations, appear to be tissue type (Myers et al., 1997, 1998; Furnari et al., 1998; associated with multiorgan involvement. Maehama and Dixon, 1998; Stambolic et al., 1998; BRRS (MIM 153480) and CS were originally thought Weng et al., 1999, 2001a–d, 2002). to be distinct clinical entities, but the discovery of PTEN Germline intragenic mutations in PTEN are found in mutations in approximately 60% of patients with BRRS 80% of individuals meeting the ICC criteria (Marsh shows that these represent different phenotypic expres- et al., 1998). Among CS probands found not to have sions of the same genotype (Marsh et al., 1997). Of those PCR-detectable intragenic mutations, approximately without intragenic PCR-detectable mutations, approxi- 10% have germline mutations in the PTEN promoter, mately 10% have large deletions (Zhou et al., 2003). which have been shown to activate Akt (Zhou et al., Hallmark features of BRRS include pigmented macules 2003). In a series of 37 CS probands, almost 70% of of the glans penis, haemangioma, lipomatosis, mental mutations were found in exons 5, 7, and 8, and included retardation, and developmental delay. Genotype–pheno- nonsense mutations, frameshift insertions and deletions, type analyses in a series of 43 BRRS probands revealed missense mutations, and splice-site mutations (Marsh an overlap in mutational spectra between BRRS and CS, et al., 1998). Approximately 40% of all mutations thus formally demonstrating allelism (Marsh et al., are localized to exon 5, which includes the phosphatase 1999), although CS-associated mutations tended to occur core motif, although exon 5 only represents 20% of in the 50 five exons and BRRS-associated mutations tend the coding sequence (reviewed in Marsh et al., 1998; towards the 30 exons (reviewed in Eng, 2003). Further, Eng, 2003). The clustering of mutations in exon 5 likely the presence of a mutation in an individual with BRRS reflects the importance of the core of the phosphatase increased the risk for breast tumour formation (Marsh domain. Indeed, the majority of missense mutations et al., 1999). Thus, in a syndrome not previously thought occur in the core motif (reviewed in Eng, 2003). to be associated with malignancy, the presence of a Similarly, mutations in exons 7 and 8 not only disrupt germline PTEN mutation in BRRS would suggest an phosphatase function but also are thought to disrupt increased risk of neoplasia, perhaps similar to CS. There phosphorylation sites. Genotype–phenotype analyses exist families with features of both CS and BRRS as well. revealed an association between the presence of PTEN To date, 495% of such overlap families have been mutation and risk of breast cancer (Marsh et al., 1998). found to have germline PTEN mutations (Marsh et al., Further, mutations within the phosphatase core motif 1998, 1999; Eng, 2003) (C Eng et al., unpublished data).

Oncogene Review of 10 highly penetrant cancer syndromes R Nagy et al 6456 Li–Fraumeni syndrome upregulated in response to cellular stress (e.g. DNA damage, viral infection), which in turn causes cell cycle Li–Fraumeni syndrome (LFS, MIM 151623) was first arrest at the G1 phase, allowing for DNA repair or described in 1969 in four families with a clustering of apoptosis. In large part, p53 function is mediated soft-tissue sarcomas, early-onset breast cancer, and through direct transcriptional regulation of downstream other malignancies in young children and adults (Li target genes. However, p53 has also been shown to and Fraumeni, 1969). In 1990, germline mutations in the contribute directly to differentiation (Rotter et al., TP53 tumour suppressor gene (also known as p53) were 1994), senescence (Vojta and Barrett, 1995; Wynford- identified in six LFS families (Malkin et al., 1990; Thomas, 1999), and angiogenesis (Bouck, 1996). Tight Srivastava et al., 1990), and since that time, approxi- control of p53 expression, activation, and stability is mately 185 families have been reported in the literature critical and has been shown to occur at the level of worldwide (reviewed in Nichols et al., 2001). The major transcription, translation, and post-translational mod- component cancers of LFS are sarcomas, breast cancer, ification by a number of proteins. For example, MDM2 brain tumours, adrenocortical carcinoma, and acute mediates p53 degradation through an auto-feedback leukaemias (Lynch et al., 1978; Tomlinson and Bulli- loop. Kinases such as ATM and CHEK2 (also known as more, 1987; Li et al., 1988). Other associated cancers hCHK2) can phosphorylate and thus stabilize the p53 may include Wilms’ tumour, cancers of the colon, protein (reviewed in Ashcroft and Vousden, 1999). As a stomach, lung, and pancreas, as well as melanoma and significant proportion of families with LFS and LFL do gonadal germ cell tumours (Strong et al., 1987; Li et al., not carry mutations in the TP53 gene, these genes and 1988; Hartley et al., 1993; Varley et al., 1997; Birch et al., others in the pathway are obvious candidates. Such 2001; Nichols et al., 2001), although some of these are possibilities are being investigated, especially after the isolated observations in a single family and thus their discovery of both missense and frameshift mutations in exact frequency in mutation carriers is unknown. the CHEK2 gene in a small number of LFS and LFL Penetrance in LFS is almost complete and appears families, as well as site-specific breast cancer families to be gender-dependent. In a recent study, the lifetime (Consortium, 2002; Sodha et al., 2002; Meijers-Heijboer penetrance for a first cancer was 12, 35, 52, and 80% by et al., 2003; Schutte et al., 2003). However, further ages 20, 30, 40, and 50 years, respectively (Hwang et al., studies are needed to determine the clinical significance 2003). When analysed by gender, females in this cohort of these findings. had a higher lifetime risk of developing cancer (93 vs Germline TP53 mutations have been identified 68% by age 50) and an earlier age at first-cancer throughout the coding region, with the majority diagnosis (mean age at diagnosis, 29 vs 40 years). The (B75%) occurring in exons 5–8 (Frebourg et al., 1995; risk of multiple primary cancers is also increased (Strong Varley et al., 1997). In contrast to other cancer et al., 1987; Garber et al., 1991; Hisada et al., 1998). syndromes, missense mutations are the most common According to one study of 24 LFS families, of 200 variety in LFS (Varley, 2003). The mutation frequency individuals with a primary cancer diagnosis, 30 (15%) in families meeting the standard clinical criteria for LFS developed a second cancer, 8 (4%) developed a third is 70–80% in most clinical laboratories (Varley et al., cancer, and 4 (2%) developed a fourth (Hisada et al., 1997; Varley, 2003). In families meeting the LFL criteria 1998). Clinical criteria for LFS and its variant form, the frequency is lower: 8% using the Eeles criteria and Li–Fraumeni-like syndrome (LFL, also called variant- 22–40% using the Birch criteria (Varley et al., 1997; LFS), have been developed and are listed in Table 7a Bougeard et al., 2001; Varley, 2003) (Table 7a and b). and b (Li et al., 1988; Birch et al., 1994; Eeles, 1995). Genotype–phenotype correlations have been observed The TP53 gene at chromosome 17p13.1 contains 11 in some studies but not in others. For example, in one exons and encodes a 53 kDa protein (p53). p53 is study, families with missense mutations in the core

Table 7 Clinical criteria for the diagnosis of LFS and LFL (a) Clinical criteria for the diagnosis of LFS (Li and Fraumeni, 1969) An individual (index case) with a sarcoma diagnosed before age 45 years, and A first-degree relative with any cancer before age 45 years, and A third family member who is a first- of second-degree relative with either a sarcoma diagnosed at any age or any cancer diagnosed before age 45 years

(b) Clinical criteria for the diagnosis of LFL (Birch et al., 1994; Eeles, 1995) Birch’s definition of LFL: A proband with any childhood cancer or sarcoma, brain tumour, or adrenal cortical tumour diagnosed under age 45 years, and A first- or second-degree relative with a typical LFS cancer (sarcoma, breast cancer, brain tumour, adrenal cortical tumour, or acute leukaemia) at any age, and An additional first- or second-degree relative with any cancer under the age of 60 years

Eeles definition of LFL: Two first- or second-degree relatives with LFS-related malignancies (sarcoma, breast cancer, malignant brain tumour, adrenal cortical carcinoma, or acute leukaemia) at any age

Oncogene Review of 10 highly penetrant cancer syndromes R Nagy et al 6457 DNA-binding domain tended to have an overall higher tumours. Familial MEN 1 is defined as at least one cancer incidence (particularly of breast and CNS MEN 1 case plus at least one first-degree relative with tumours) with an earlier age at onset, as compared to one of these three tumours (Trump et al., 1996; families with protein-truncating or -inactivating muta- Chandrasekharappa et al., 1997; Brandi et al., 2001). tions, or families with no mutation at all (Birch et al., The age-related penetrance of MEN 1 is 45% at age 1998). In contrast, a study of 56 TP53 mutation-positive 30 years, 82% at age 50 years, and 96% at age 70 years individuals from 107 kindreds ascertained through cases (Trump et al., 1996; Carty et al., 1998). Primary of childhood soft-tissue sarcoma reported no difference hyperparathyroidism (HPT) is the most common, and in phenotype between patients with missense mutations often the earliest manifestation, occurring in 80–100% vs truncating mutations (Hwang et al., 2003). Similarly, of patients by age 50 (Benson et al., 1987; Brandi et al., Olivier et al. (2003) found no differences in phenotype 1987; Thakker, 1995; Trump et al., 1996). These between mutation type (missense vs truncating), but did tumours are typically multiglandular and often hyper- find significant differences depending on the location plastic, in contrast to the solitary adenoma seen in of the mutation, specifically for brain tumours and sporadic primary HPT (Chandrasekharappa and Teh, adrenocortical tumours. Brain tumours were more likely 2001). In addition, the average age at onset of HPT is 30 to be associated with mutations in loops 1 and 2 of the years earlier in patients with MEN 1 than in the general p53 protein, which together form a complex with zinc population (20–25 vs 50 years). Parathyroid carcinoma that then binds to the minor groove of its target DNA. is not known to be associated with MEN 1. Adrenocortical tumours were more strongly associated Pancreatic islet cell tumours, usually gastrinomas and with mutations in the non-DNA-binding domain vs the insulinomas, and less commonly VIPomas (vasoactive DNA-binding domain. Differences in patient accrual, intestinal peptide), glucagonomas and somatistatino- study design, and mutation site classification may have mas, are the second most common endocrine manifesta- contributed to these disparate findings, and thus more tion, occurring in up to 30–80% of patients by age 40 studies are needed to clarify this issue. (Thakker, 1995; Trump et al., 1996). These are usually The frequency of germline TP53 mutations in patients multicentric and can arise in the pancreas or, more with multiple primary cancers unselected for family commonly, as small (o0.5 cm) foci throughout the history (Malkin et al., 1992; McIntyre et al., 1994), as duodenum (Pipeleers-Marichal et al., 1990). Gastrino- well as those with ‘isolated’ LFS component tumours, mas represent 50% of the pancreatic islet cell tumours in has been extensively studied. While only 1% of isolated MEN 1 and are the major cause of morbidity and early-onset breast cancer cases will harbour a germline mortality in MEN 1 patients (Trump et al., 1996; TP53 mutation (Borresen et al., 1992; Sidransky et al., Norton et al., 1999). Most result in peptic ulcer disease 1992; Lalloo et al., 2003), the frequency is higher in (Zollinger–Ellison syndrome) and half are malignant at sporadic osteosarcomas (2–3%) (McIntyre et al., 1994), the time of diagnosis (Pipeleers-Marichal et al., 1990; rhabdomyosarcoma (9%) (Diller et al., 1995), and brain Weber et al., 1995; Norton et al., 1999). Nonfunctional tumours (2–10%) (Felix et al., 1995; Li et al., 1995). tumours of the entero-pancreas, some of which produce Perhaps the most striking association occurs in cases of pancreatic polypeptide, are seen in 20% of patients childhood adrenocortical carcinoma (ACC). In a series (Skosgeid et al., 1994; Marx, 2002). of 14 ACC patients unselected for family history, 11 Approximately 15–50% of MEN 1 patients will (82%) families carried a germline TP53 mutation. develop a pituitary tumour (Thakker, 1995; Trump Interestingly, the same two mutations (at codons 152 et al., 1996). Two-thirds are microadenomas (o1.0 cm and 158) were present in 9 of the 11 mutation-positive in diameter) and the majority are prolactin-secreting cases. In another series of 36 cases of childhood ACC in (Corbetta et al., 1997). Other manifestations include southern Brazil, 35 carried an identical R337H mutation carcinoids of the foregut (typically bronchial or thymic) (Ribeiro et al., 2001). There was no evidence of a (Teh et al., 1998), skin tumours including lipomas founder effect in either study and the cancer family (30%), facial angiomas (85%), and collagenomas (70%) history in mutation-positive cases was not striking, (Thakker, 1995; Darling et al., 1997; Marx, 2002) and suggesting a low-penetrance and possibly tissue-specific adrenal cortical lesions, including cortical adenomas, mutation at these positions. diffuse or nodular hyperplasia or rarely carcinoma. These adrenal lesions do not show LOH for the MEN 1 locus and might represent a secondary phenomenon Multiple endocrine neoplasia type 1 (Skogseid et al., 1992; Burgess et al., 1996). Thyroid adenomas, phaeochromocytoma (PC) (usually unilat- Multiple endocrine neoplasia type 1 (MEN 1, MIM eral), spinal ependymoma, and leiomyoma have also 131100) is an autosomal dominant syndrome with an been reported but their frequency is not known (Ballard estimated incidence in the general population on the et al., 1964; Dackiw et al., 1999). order of 1–2/100 000 (Chandrasekharappa and Teh, The prevalence of MEN 1 among patients with 2001). The major endocrine features of MEN 1 are apparently sporadic component tumours varies but is parathyroid adenomas, entero-pancreatic endocrine quite high for some tumour types. Approximately one- tumours, and pituitary tumours. As defined by the third of patients with Zollinger–Ellison syndrome will consensus diagnostic criteria, a diagnosis of MEN 1 is have a clinical diagnosis of MEN 1 (Bardram and Stage, made in a person with two of the three major endocrine 1985; Roy et al., 2000). Only 2–3% of patients with

Oncogene Review of 10 highly penetrant cancer syndromes R Nagy et al 6458 primary HPT have MEN 1 (Uchino et al., 2000), in other FIHP families is of interest (Carpten et al., although familial isolated hyperparathyroidism (FIHP) 2002). Given the differential risks between these three is allelic to MEN 1, with 20% of probands harbouring a conditions as well as the increased risk of parathyroid germline MEN1 mutation (see below) (Pannett et al., carcinoma in HPT–JT, genetic diagnosis in a patient 2003). Lastly, among patients with pituitary tumours, presenting with early-onset primary HPT may play a the prevalence of MEN 1 is 2.5–5% (Scheithauer et al., larger role in the management of these patients and their 1987; Corbetta et al., 1997), but is as high as 14% in families. patients with prolactinoma (Corbetta et al., 1997). These results underscore the importance of collecting a thorough medical and family history in patients with a Multiple endocrine neoplasia type 2 diagnosis of an MEN 1-associated endocrine tumour. Germline mutations in MEN1, on 11q13 and encod- Multiple endocrine neoplasia type 2 (MEN 2) is an ing menin, have been found in 60–70% of MEN 1 autosomal dominant cancer syndrome characterized by probands (Larsson et al., 1988; Chandrasekharappa medullary thyroid cancer (MTC), PC, and/or HPT. et al., 1997). Loss of the wild-type allele in many familial Historically, MEN 2 has been divided into three and sporadic MEN 1-associated tumours, as well as the subtypes depending on clinical features: MEN 2A fact that most mutations result in protein truncation, (MIM 171400), MEN 2B (MIM 162300), and familial suggests that MEN1 is a tumour suppressor gene. The medullary thyroid carcinoma (FMTC, MIM 155240). exact role of menin is not currently known, but its MEN 2A classically comprises MTC in 100% of localization to the nucleus and its interactions with affected individuals, PC in 50%, and HPT in 15–30% proteins such as JunD, NF-kB, Smad3, and RelA, (reviewed by Gimm, 2001). MEN 2B is similar to MEN among others, suggest that it may play a role in 2A except that the average age of tumour onset is 10 transcription regulation (reviewed in Poisson et al., years younger than that for MEN 2A, that HPT is not 2003). A recent study suggests that in murine embryonic clinically manifest and that other features such as fibroblasts, wild-type menin may promote apoptosis marfanoid habitus and mucosal neuromatosis are through the caspase-mediated cascade by upregulating present (Gorlin et al., 1968). FMTC is operationally transcription of procaspase 8 (Schnepp et al., 2003). It is defined as the presence of MTC in the absence of PC also possible that it plays a role in other regulatory and HPT (Farndon et al., 1986). All three subtypes have pathways that lead to the control of cell growth and/or been mapped to chromosome sub-band 10q11.2 by genomic integrity, but this remains to be seen. linkage analyses, and are caused by germline mutations Over 300 MEN1 mutations have been identified to of the RET (REarranged during Transfection) proto- date and these are scattered across the entire coding oncogene (Mathew et al., 1987; Simpson et al., 1987; region. The majority of these are nonsense or frameshift Gardner et al., 1993; Mulligan et al., 1993). RET was the mutations and the remainder are missense or in-frame first proto-oncogene to be implicated in an inherited deletions that lead to expression of an altered protein. cancer susceptibility syndrome. There is currently no evidence of genotype–phenotype Before identification of RET as the MEN 2 suscept- correlations and inter- and intrafamilial variability is ibility gene, the clinical penetrance of MEN 2A was said the rule (Giraud et al., 1998; Wautot et al., 2002). to be 70% by the age of 70 years (Ponder et al., 1988). Identification of the familial mutation can be used for After the putative susceptibility locus was found, the predictive testing of at-risk family members. Since many biochemically induced penetrance of MEN 2A was of the tumours in MEN 1 are under- or misdiagnosed, found to be 100% by the age of 70 years (Easton et al., identifying mutation carriers within an MEN 1 family 1989). Likewise, original epidemiology studies suggested can allow for early detection and treatment. In addition, that approximately 25% of all MTC presentations were genetic testing for MEN1 mutations can be used to due to MEN 2. After RET was identified, several series distinguish between it and other forms of hereditary examined the frequency of unexpected germline RET HPT, such as FIHP (MIM 145000) and hyperparathyr- mutations in apparently sporadic MTC. When indivi- oidism–jaw tumour syndrome (HPT–JT, MIM 145001). duals with MTC were tested without taking a good HPT–JT, which is caused by germline mutations in the family history or excluding syndromic features, the HRPT2 gene, is associated with primary HPT, ossifying mutation frequency was approximately 25% (Decker lesions of the maxilla and mandible, and renal lesions, et al., 1995). However, several other series accruing usually bilateral renal cysts, hamartomas and, in some MTC cases with no family history and no syndromic cases, Wilms’ tumour (Teh et al., 1996; Carpten et al., features reveal that the unexpected germline RET 2002). Unlike MEN1, HPT–JT is associated with an mutation frequency ranges from 5 to 10% (Eng et al., increased risk of parathyroid carcinoma (Marx, 2000). 1995a; Wohlik et al., 1996; Schuffenecker et al., 1997; On the other hand, as its name suggests, FIHP is Wiench et al., 2001). A population-based series of characterized by isolated primary HPT with no addi- apparently sporadic PC, defined as no family history tional endocrine features, and in some families, FIHP is and no syndromic features, suggests an B5% occult the initial diagnosis of what later develops into MEN 1. germline RET mutation frequency (Neumann et al., While 20% of families with a clinical diagnosis of FIHP 2002). carry germline MEN1 mutations (Miedlich et al., 2001), The RET gene is comprised of 21 exons and encodes the recent identification of germline HRPT2 mutations a transmembrane receptor tyrosine kinase expressed in

Oncogene Review of 10 highly penetrant cancer syndromes R Nagy et al 6459 tissues and tumours derived mainly from the neural crest families have not been found to have C634R mutations, (Takahashi et al., 1985, 1988; Takahashi and Cooper, but C634Y and other 634 mutations (Eng et al., 1996). 1987; Pachnis et al., 1993; Nakamura et al., 1994; Germline mutations probably unique to FMTC include Tsuzuki et al., 1995). The structure of the RET receptor E768D (exon 13), V804L and V804M (exon 14), although is like that of most receptor tyrosine kinases with a large one family segregating V804L has been described with extracellular domain, comprising a cysteine-rich domain older-onset unilateral PC in two members (Eng et al., and a cadherin-like domain, a transmembrane domain, 1996; Nilsson et al., 1999). and an intracellular tyrosine kinase domain (Pasini et al., Germline M918T and A883F mutations occur in 95% 1995; Eng, 1999). However, the RET receptor is unique and B2%, respectively, of MEN 2B patients (Eng et al., in that it requires a multicomponent complex to trigger 1996; Gimm et al., 1997; Smith et al., 1997). These two activation. RET has to bind one of four GFRa family mutations are unique to MEN 2B and have never been of GPI-linked coreceptors before binding one of four observed in MEN 2A or FMTC. Interestingly, at least members of the glial cell line-derived neurotrophic one MEN 2B family appears to carry a V804M factor family of ligands (GDNF, neurturin, persephin, mutation in the presence of a RET variant of unknown and artemin) in a heterohexameric complex (Durbec significance (Miyauchi et al., 1999). et al., 1996; Jing et al., 1996; Kotzbauer et al., 1996; Discovering that RET is the susceptibility gene for Treanor et al., 1996; Trupp et al., 1996; Vega et al., MEN 2 also led to the realization that variable 1996; Baloh et al., 1997; Buj-Bello et al., 1997; Klein penetrance characterized various genotypes. For exam- et al., 1997). When RET is activated, it autopho- ple, it has now become obvious that RET codons 918, sphorylates and phosphorylates such downstream mo- 883, and 634 mutations have the highest penetrance, lecules as Shc (Borrello et al., 1994; van Weering et al., predisposing to MEN 2B and MEN 2A with MTC, PC, 1995). RET signals down a number of well-character- and HPT involvement (Eng et al., 1995a; Eng, 2000a). ized signal transduction pathways, including the MAP In contrast, germline V804M mutations and perhaps kinase–RAS–RAF and phosphoinositide 3-kinase path- cysteine codon 609 mutations have the lowest pene- ways (van Weering and Bos, 1998; Besset et al., 2000). trance and the older ages of onset (Eng et al., 1996; MEN 2A- and FMTC-related mutations affecting Shannon et al., 1999). Mutations at codons 611–620 cysteine codons result in disulphide bond-mediated have a broad range of penetrance and expressivity. inter-receptor binding and thus constitutive activation Taken together, these data suggest that each of the (Borrello et al., 1995; Santoro et al., 1995). Interestingly, component organs has a different threshold for trans- colony forming assays revealed that the C634R muta- formation to neoplasia, with the highest threshold in the tion had a higher transformation rate and/or signal parathyroid glands and the lowest in the C-cells of the activation than exon 10 cysteine mutations, for example, thyroid, the precursor cells of MTC. C620R (Santoro et al., 1995; Carlomagno et al., 1997; Although gain-of-function RET mutations cause Ito et al., 1997). The MEN 2B-related M918T mutation MEN 2, studies have shown that loss-of-function RET alters a highly conserved residue in the catalytic core of mutations result in Hirschsprung disease (HSCR, MIM the tyrosine kinase domain by altering substrate 142623). Hirschsprung disease is a frequent (1 in 5000 specificity (Songyang et al., 1995). Mutations in codon live births) congenital intestinal malformation charac- 768 likely affect substrate specificity and perhaps ATP terized by the absence of enteric innervation in the binding (Eng et al., 1995b). hindgut, resulting in functional intestinal obstruction. Germline RET mutations have been identified in Highly selected series of HSCR cases have yielded a approximately 95% of all MEN 2, with 98% of MEN 30–50% germline RET mutation frequency in familial 2A probands found to have a mutation, 97% in MEN cases and a 15–30% frequency in sporadic HSCR 2B and 85% in FMTC (Eng et al., 1996; Gimm et al., (reviewed by Eng, 1999). However, population-based 1997; Smith et al., 1997) (Figure 3). The characteristic mutational spectrum found in MEN 2A includes missense mutations in one of cysteine codons 609, 611, 618, 620 (exon 10), or 634 (exon 11) (Mulligan et al., 1994b; Eng et al., 1996). Approximately 85% of MEN 2A individuals carry a codon 634 mutation (Eng et al., 1996). Genotype–phenotype analyses reveal that codon 634 mutations are associated with the presence of PC and HPT (Eng et al., 1996). In particular, the C634R mutation is likely associated with the development of HPT (Mulligan et al., 1994b; Eng et al., 1996; Schuffenecker et al., 1998). Rare ‘one of’ missense mutations seen in MEN 2A include those involving codons 630 and 790 (Eng et al., 1996; Eng, 1999). FMTC-associated mutations occur at the same cysteine codons as those in MEN 2A, although mutations at codons 609–620 are more propor- tionately frequent in FMTC than MEN 2A (Figure 3). Figure 3 Relative frequency and distribution of germline RET Consistent with the C634R–HPT association, FMTC mutations in MEN 2, comprising MEN 2A, MEN 2B, and FMTC

Oncogene Review of 10 highly penetrant cancer syndromes R Nagy et al 6460 series suggest that 10–30% of familial HSCR are due to cies and age of onset of each of the associated lesions germline loss-of-function RET mutations and perhaps (Lamiell et al., 1989; Maddock et al., 1996). The most 3% of sporadic cases have such mutations as well. common manifestations of VHL are retinal haemangio- Although these mutations are generally scattered mas (49–57%), haemangioblastomas of the cerebellum throughout the gene, a number of kindreds have been (35–59%) and spinal cord (B14%), clear cell renal described with germline RET mutation in codons 609, carcinoma (24–47%), and PC (7–19%). Pancreatic cysts 618, and 620, with co-segregation of both MEN 2A/ and tumours (16%), endolymphatic sac tumours (11%), FMTC and HSCR disease phenotypes (Mulligan et al., and papillary cystadenoma of the epididymis (15%) 1994a). There are other families with HSCR as the only have also been described (Neumann, 1987; Maher et al., manifestation, although these families have nucleotide 1990; Megerian et al., 1995). In general, these lesions substitutions in the cysteine 609 and 620 codons only occur much earlier than in the general population. For (Mulligan et al., 1994a). example, the mean age at diagnosis of cerebellar Functional data have supplied some clues in an haemangioblastoma is 29710 years and for renal cell attempt to explain this apparent contradiction. For carcinoma is 44.07years (Lamiell et al., 1989; Maher one, it has been shown that missense mutations of the et al., 1991), tumours which typically occur in the fourth more 50 codons, such as 609, 611, 618, and 620, result in or fifth decades of life (Murphy et al., 1995). In addition less migration of these mutant receptors to the cell to presenting at an earlier age, these tumours tend to be surface (Ito et al., 1997; Eng, 2001a). Studies have also bilateral and/or multifocal. The clinical criteria for VHL shown that the exon 10 Cys mutations have a three- to are outlined in Table 8 (Maher et al., 1990). fivefold lower transforming activity in transfection The VHL susceptibility gene, VHL on chromosome studies of NIH 3T3 cells than the C634R mutant sub-band 3p26, (Latif et al., 1993), is a tumour (Carlomagno et al., 1997; Ito et al., 1997). Taken suppressor gene that comprises three exons and encodes together, this suggests that the MEN 2A/FMTC two isoforms: a 24–30 kDa protein and an 18–20 kDa phenotype may be a direct consequence of the differ- protein, which is the result of a second start codon at ences in penetrance of each mutation type. In this amino-acid position 54 within the open reading frame scenario, the codon 634 mutations will more often result (Iliopoulos et al., 1998; Schoenfeld et al., 1998). These in full manifestation of the classic MEN 2A phenotype two isoforms are collectively referred to as pVHL. Both (MTC, PC, and HPT) due to the greater availability of are biologically active, although differentially expressed, mature, albeit mutant, receptors on the cell surface. In and inactivation of both is required for tumour contrast, the exon 10 mutations allow a lesser amount formation, as demonstrated through in vitro studies of available receptors on the cell surface, so less RET (Iliopoulos et al., 1998; Schoenfeld et al., 1998). In dimerization, activation, and transformation, leading to support of these data are the interesting observations a less severe phenotype. This ‘threshold’ effect on that all disease-associated mutations map carboxy- disease phenotype would be invariably dependent on terminal to the second start codon (Maher and Kaelin, the tissue involved, and the particular stage of develop- 1997) and the highest degree of amino-acid conservation ment (Eng, 2001a). For those families with both MEN across species occurs in this region (Latif et al., 1993; 2/FMTC and HSCR, which have exon 10 alteration, it is Duan et al., 1995). Approximately 28% of mutations in plausible to speculate that the developing enteric ganglia the VHL gene are partial or complete deletions (Stolle require a certain number of receptors, while it is et al., 1998). The remaining 72% are small deletions/ sufficient for the presence of constitutively active insertions or point mutations. Therefore, genetic testing receptor, whatever the levels, for neoplasia to occur. for VHL should include a combination of quantitative Clearly, however, the actual levels of available receptor Southern blot analysis and DNA sequencing. The seem to affect penetrance and expressivity.

Table 8 Clinical criteria for von Hippel–Lindau disease von Hippel–Lindau disease An isolated case (i.e. no known family history of VHL) with two or more of the following characteristic lesions: von Hippel–Lindau disease (VHL, MIM 193300) is Two or more haemangioblastomas of the retina or brain, or an inherited multisystem disease predisposing to retinal A single haemangioblastoma with one of the following: and central nervous system haemangioblastomas, renal Renal, pancreatic, or epididymal cysts cell carcinoma, PC, pancreatic islet cell tumours, and Renal cell carcinoma Adrenal or extra-adrenal phaeochromocytoma endolymphatic sac tumours. It has an estimated birth Endolymphatic sac tumours incidence of 1 in 36 000 per year (Maher et al., 1991) Neuroendocrine tumours of the pancreas and is inherited in an autosomal dominant manner with a high degree of inter- and intrafamilial variability An individual with a family history of VHL who has one or more of the following: (Neumann and Wiestler, 1991). The penetrance is Retinal angioma age-dependent, but reaches 95–100% by age 65 (Maher CNS haemangioblastoma et al., 1991). Phaeochromocytoma Two large studies comprising approximately 700 Multiple renal or pancreatic cysts patients with VHL, including one six-generation kindred Epididymal cystadenoma Renal cell carcinoma before age 60 with 43 affected family members, reviewed the frequen-

Oncogene Review of 10 highly penetrant cancer syndromes R Nagy et al 6461 Table 9 Genotype–phenotype correlations in VHL Disease type Tumour phenotype Mutation type Molecular defect

1 HAB, RCC (pc^) Deletion or nonsense; protein-folding mutation Abnormal HIF regulation 2A HAB, PC (rcc^) Missense Abnormal HIF regulation 2B HAB, RCC, PC Missense Abnormal HIF regulation 2C PC only Missense HIF regulation normal; matrix-assembly defect

HAB, haemangioblastoma; RCC, renal cell carcincoma; PC, phaeochromocytoma. ^ indicates low risk of this tumour in disease subtype sensitivity of this combined approach is nearly 100% retain the ability to regulate HIF1, but lose the ability to when performed on patients with a clinical diagnosis of bind fibronectin, which may in turn dysregulate extra- VHL (Stolle et al., 1998). cellular matrix formation. In contrast, mutations that Clear genotype–phenotype correlations have been cause haemangioblastoma and renal cell carcinoma described for VHL. VHL families are categorized into (types 1, 2A, and 2B) are deficient in HIF1 degradation two subtypes based on a low (type 1) or high (type 2) (Table 9). These studies suggest that loss of HIF1 risk of PC (Table 9). VHL type 2 has been further function may lead to an increased risk of the vascular- divided based upon a low risk (type 2A) or high risk ized tumours typically seen in VHL, while the under- (type 2B) of renal cell carcinoma (Maher et al., 1990). In lying mechanism of PC formation in VHL occurs a third subtype, VHL 2C, PC is the only manifestation. through a different pathway, possibly fibronectin– Of those with VHL type 1, 50% will have large deletions matrix assembly. or truncating mutations, while the majority (B95%) of patients with VHL type 2 (with PC) have missense mutations (Chen et al., 1995; Kaelin and Maher, 1998). Conclusions Interestingly, in a population-based study of families fitting the VHL type 2C description (isolated PC with The discoveries generated by the investigation of no other syndromic features), 11% had a germline inherited cancer syndromes, some of which are high- VHL mutation (Neumann et al., 2002). Some have lighted here, transcend the field of cancer genetics. First, suggested that missense mutations in VHL may result although highly penetrant cancer susceptibility alleles in a ‘gain of function’ or that the development of PC is are rare in the general population, the information the result of partial loss of pVHL function, rather than gained through the discovery and characterization of complete loss. genes such as RET, APC, PTEN,andTP53 can be (and The VHL protein (pVHL) has been implicated in a is being) applied to the study of sporadic tumours as variety of cellular functions including extracellular well. Second, while genotype–phenotype correlations matrix formation and cell cycle exit (Gnarra et al., will continue to assist clinicians in counselling at-risk 1994; Ohh et al., 1998; Pause et al., 1998). Perhaps its families, they will also shed light on the molecular most well-characterized role is the regulation of pathogenesis and tissue specificity of such mutations. In hypoxia-inducible factor 1 (HIF1). HIF1 is a hetero- addition, some of the aforementioned molecular path- dimer (with a- and b-subunits), which in hypoxic ways have been implicated in other disease processes conditions binds DNA and activates transcription of a (e.g. HIF1 in ischaemic heart disease and type II BMP number of downstream genes that are involved in energy receptors in primary pulmonary hypertension) and metabolism, angiogenesis, and apoptosis. These include therefore these discoveries will no doubt have a broader vascular endothelial growth factor (VEGF) and platelet- impact on the practice of medicine. And lastly, these derived growth factor B chain (PDGF B), among many studies may allow for the development of targeted others. When complexed with elongin B, elongin C, and molecular-based interventions, which, in theory, may Cul2, pVHL has been shown to bind directly HIF1a and serve as therapeutic adjuncts not only in cancer but also target this for ubiquitylation and degradation by the other multifactorial conditions such as diabetes and 26S proteosome (Maxwell et al., 1999). Cells lacking heart disease. pVHL are unable to degrade HIF1a, which leads to the constitutive overexpression of hypoxia-inducible mRNAs such as VEGF and PDGF B (Iliopoulos et al., 1996; Levy et al., 1996). When wild-type VHL is Note added in proof transfected back into VHLÀ/À cells in the presence of oxygen, this overexpression is suppressed. Recently, it was reported that among seven unrelated Several recent lines of evidence indicate that pVHL cases of JPS individuals with germline MADH4 muta- may act in a tissue-specific manner and that it is not tions, all were found to have hereditary haemorrhagic only mutation type (i.e. deletion vs missense) but its telangectasia (HHT) (Gallione et al., 2004). differential effects on various pVHL-dependent path- Gallione CJ, Repetto GM, Legius E, Rustgi AK, ways that determine the tumour phenotype (Clifford Schelley SL, Tejpar S, Mitchell G, Drouin E, Wester- et al., 2001; Hoffman et al., 2001). For example, mann CJJ and Marchuk DA. (2004) Lancet, 363, mutations in families with VHL type 2C (PC only) 852–859.

Oncogene Review of 10 highly penetrant cancer syndromes R Nagy et al 6462 Acknowledgements part by the American Cancer Society, Department of Defense We are grateful to Doreen Agnese, Carrie Drovdlic, Heather US Army Breast and Prostate Cancer Research Programs, Hampel, Rob Pilarski, and Leigha Senter for critical review Susan G Komen Breast Cancer Research Foundation, of this manuscript. We thank Ross Waite for his assistance National Cancer Institute, National Institutes of Health, State with electronic artwork. CE is the recipient of a Doris Duke of Ohio Biomedical Research and Technology Transfer Fund Distinguished Clinical Scientist Award and is supported in and V Foundation.

References

Aaltonen LA, Jarvinen H and Gruber SB. (2000). Pathology Birch JM, Blair V, Kelsey AM, Evans DG, Harris M, Tricker and Genetics of Tumours of the Digestive System. World KJ and Varley JM. (1998). Oncogene, 17, 1061–1068. Health Organisation Classification of Tumors. Aaltonen Birch JM, Hartley AL, Trickier KJ, Prosser J, Condie A, LA and Hamilton SR (eds). IARC Press, Lyon, France, Kelsey AM, Harris M, Jones PH, Binchy A and Crowther pp. 74–76. D. (1994). Cancer Res., 54, 1298–1304. Aaltonen LA, Salovaara R, Kristo P, Canzian F, Hemmenki Bisgaard M, Jager A, Myrhoj T, Bernstein I and Nielsen F. A, Peltomaki P, Chadwick RB, Kaariainen H, Eskelinen M, (2002). Hum. Mutat., 20, 20–27. Jarvinen H, Mecklin J-P and de la Chapelle A. (1998). Boardman L, Thibodeau S, Schaid D, Lindor N, McDonnell N. Engl. J. Med., 338, 1481–1487. S, Burgart L, Ahlquist D, Podratz K, Pittelkow M and Aarnio M, Sanikala R, Pukkala E, Salovaara R, Aaltonen LA, Hartmann L. (1998). Ann. Intern. Med., 128, 896–899. de la Chapelle A, Peltomaki P and Jarvinen HJ. (1999a). Int. Bodmer WF, Bailey CJ, Bodmer J, Bussey HJR, Ellis A, J. Cancer, 81, 214–218. Gorman P, Lucibello FC, Murday VA, Rider SH, Scambler Aarnio M, Sankila R and Pukkala E. (1999b). Int. J. Cancer, P, Sheer D, Solomon E and Spurr NK. (1987). Nature, 328, 81, 214–218. 614–616. Al-Tassan N, Chmiel N, Maynard J, Fleming N, Livingston A, Borrello MG, Pelicci G, Arighi E, DeFillippis L, Greco A, Williams G, Hodges A, Davies D, David S, Sampson J and Bongarzone I, Rizzetti MG, Pelicci PG and Pierotti MA. Cheadle J. (2002). Nat. Genet., 30, 227–232. (1994). Oncogene, 9, 1661–1668. Andersen TI, Borresen AL and Moller P. (1996). Am. J. Hum. Borrello MG, Smith DP, Pasini B, Bongarzone I, Greco A, Genet., 59, 486–487. Lorenzo MJ, Arighi E, Miranda C, Eng C, Alberti L, Antoniou AC, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Bocciardi R, Mondellini P, Scopsi L, Romeo G, Ponder BAJ Hopper JL, Loman N, Olsson H, Johannsson O, Borg A, and Pierotti MA. (1995). Oncogene, 11, 2419–2427. Pasini B, Radice P, Manoukian S, Eccles DM, Tang N, Olah Borresen AL, Andersen TI, Garber J, Barbier-Piraux E, Anton-Culver H, Warner E, Lubinski J, Gronwald J, N, Thorlacius S, Eyfjord J, Ottestad L, Smith-Sorensen Gorski B, Tulinius H, Thorlacius S, Eerola H, Nevanlinna B, Hovig E and Malkin D. (1992). Cancer Res., 52, H, Syrjakoski K, Kallioneimi OP, Thompson D, Evans C, 3234–3236. Peto J, Lalloo F, Evans DG and Easton DF. (2003). Am. J. Bouck N. (1996). Biochim. Biophys. Acta, 1287, 63–66. Hum. Genet., 72, 1117–1130. Bougeard G, Limacher JM, Martin C, Charbonnier F, Killian Aprelikova ON, Fang BS, Meissner EG, Cotter S, Campbell A, Delattre O, Longy M, Jonveaux P, Fricker JP, Stoppa- M, Kuthiala A, Bessho M, Jensen RA and Liu ET. (1999). Lyonnet D, Flaman JM and Frebourg T. (2001). J. Med. Proc. Natl. Acad. Sci. USA, 96, 11866–11871. Genet., 38, 253–257. Ashcroft M and Vousden KH. (1999). Oncogene, 18, Brandi M, Gagel R, Angeli A, Bilezikian J, Beck-Peccoz 7637–7643. P, Bordi C, Conte-Devolx B, Falchetti A, Gheri R, Avizienyte E, Roth S, Loukola A, Hemminki A, Lothe R, Libroia A, Lips C, Lombardi G, Mannelli M, Pacini Stenwig A, Fossa S, Salovaara R and Aaltonen L. (1998). F, Ponder B, Raue F, Skogseid B, Tamburrano G, Thakker Cancer Res., 58, 2087–2090. R, Thompson N, Tommassetti P, Tonelli F, Wells S Ballard HS, Frame B and Hartsock RJ. (1964). Medicine, and Marx S. (2001). J. Clin. Endrocrinol. Metab., 86, 43, 481. 5658–5671. Baloh RH, Tansey MG, Golden JP, Creedon DJ, Heukeroth Brandi ML, Marx SJ, Aurbach GD and Fitzpatrick LA. RO, Keck CL, Zimonjic DB, Popescu NC, Johnson EM and (1987). Endocrinol. Rev., 8, 391–405. Milbrandt J. (1997). Neuron, 18, 793–802. Brose MS, Rebbeck TR, Calzone KA, Stopfer JE, Nathanson Bardram L and Stage JG. (1985). Scand. J. Gastroenterol., 20, KL and Weber BL. (2002). J. Natl. Cancer Inst., 94, 233–238. 1365–1372. Benson L, Ljunghall S, Akerstrom G and Oberg K. (1987). Buj-Bello A, Adu J, Pino´ n LGP, Horton A, Thompson J, Am. J. Med., 82, 731–737. Rosenthal A, Chinchetru M, Buchman VL and Davies AM. Bertario L, Russo A, Sala P, Eboli M, Giarola M, D’Amico F, (1997). Nature, 387, 721–724. Gismondi V, Varesco L, Pierotti M and Radice P. (2001). Bulow S, Alm T, Fausa O, Hultcrantz R, Jarvinen H and Int. J. Cancer, 95, 102–107. Vasen HFA. (1995). Int. J. Colorectal Dis., 10, 43–46. Besset V, Scott RP and Ibanez CF. (2000). J. Biol. Chem., 275, Burgess JR, Harle RA, Tucker P, Parameswaran V, Davies P, 39159–39166. Greenaway TM and Shepard JJ. (1996). Arch. Surg., 131, Bevan S, Woodford-Richens K, Rozen P, Eng C, Young J, 699–702. Dunlop M, Neale K, Phillips R, Markie D, Rodriguez-Bigas Burn J, Chapman P and Delhanty J. (1991). J. Med. Genet., 28, M, Leggett B, Sheridan E, Hodgson S, Iwama T, Eccles D, 289–296. Bodmer W, Houlston R and Tomlinson I. (1999). Gut, 45, Burt R, Bishop D, Lynch H, Rozen P and Winawer S. (1993). 406–408. Bull. WHO, 68, 655–659. Birch JM, Alston RD, McNally RJQ, Evans DGR, Kelsey Bussey H. (1975). Familial Polyposis Coli. Family Studies, AM, Harris M, Eden OB and Varley JM. (2001). Oncogene, Histopathology, Differential Diagnosis and Results of Treat- 20, 4621–4628. ment. The Johns Hopkins University Press: Baltimore, MD.

Oncogene Review of 10 highly penetrant cancer syndromes R Nagy et al 6463 Cantu J, Rivera H, Ocampo-Campos R, Bedolla N, Cortes- Desai D, Murday V, Phillips R, Neale K, Milla P and Gallegos V, Gonzalez-Mendoza A, Diaz M and Hernandez Hodgson S. (1998). J. Med. Genet., 35, 476–481. A. (1980). Cancer, 46, 223–228. Desai D, Neale K, Talbot I, Hodgson S and Phillips R. (1994). Carlomagno F, Salvatore G, Cirafici AM, Devita G, Melillo Br. J. Surg., 82, 14–17. RM, Defranciscis V, Billaud M, Fusco A and Santoro M. Diller L, Sexsmith E, Gottleib A, Li FP and Malkin D. (1995). (1997). Cancer Res., 57, 391–395. J. Clin. Invest., 95, 1606–1611. Carpten J, Robbins C, Villablanca A, Forsberg L, Presciuttini Duan DR, Pause A, Burgess WH, Aso T, Chen DYT, S, Bailey-Wilson J, Simonds W, Gillanders E, Kennedy A, Garrett KP, Conaway RC, Conaway JW, Linehan WM Chen J, Agarwal S, Sood R, Jones M, Moses T, Haven C, and Klausner RD. (1995). Science, 269, 1402–1406. Petillo D, Leotlela P, Harding B, Cameron D, Pannett A, Durbec P, Marcos-Gutierrez CV, Kilkenny C, Grigoriou M, Hoog A, Heath H, James-Newton L, Robinson B, Zarbo R, Wartiowaara K, Suvanto P, Smith D, Ponder B, Costantini Cavaco B, Wassif W, Perrier N, Rosen I, Kristoffersson U, F, Saarma M, Sariola H and Pachnis V. (1996). Nature, 381, Turnpenny P, Farnebo L, Besser G, Jackson C, Morreau H, 789–793. Trent J, Thakker R, Marx S, Teh B, Larsson C and Hobbs Easton DF, Bishop DT, Ford D, Crockford GP and the Breast M. (2002). Nat. Genet., 32, 676–680. Cancer Linkage Consortium. (1993). Am. J. Hum. Genet., Carty SE, Helm AK, Amico JA, Clarke MR, Foley TP, 52, 678–701. Watson CG and Mulvihill JJ. (1998). Surgery, 124, Easton DF, Ponder MA, Cummings T, Gagel R, Hansen HH, 1106–1114. Reichlin S, Tashjian AH, Telenius-Berg M and Ponder BAJ. Cetta F, Montalto G, Gori M, Curia M, Cama A and (1989). Am. J. Hum. Genet., 44, 208–215. Olschwang S. (2000). J. Clin. Endocrinol. Metab., 85, 286–292. Eeles R. (1995). Cancer Surv., 25, 101–124. Chadwick RB, Jiang GL, Bennington GA, Yuan B, Johnson Eng C. (1997). J. Genet. Counsel., 6, 181–191. CK, Stevens MW, Niemann TH, Peltomaki P, Huang S and Eng C. (1999). J. Clin. Oncol., 17, 380–393. de la Chapelle A. (2000). Proc. Natl. Acad. Sci. USA, 97, Eng C. (2000a). Rev. Endocrinol. Metab. Dis., 1, 283–290. 2662–2667. Eng C. (2000b). J. Med. Genet., 37, 828–830. Chan T, Yuen S, Ho J, Chan A, Kwan K, Chung L, Lam P, Eng C. (2001a). Molecular Genetics of Cancer Cowell J (ed). Tse C and Leung S. (2001). Oncogene, 20, 2976–2981. BIOS Scientific Publishers Ltd: Oxford, pp 171–194. Chandrasekharappa S and Teh B. (2001). Genetic Disorders of Eng C. (2001b). Nat. Genet., 28, 105–107. Endocrine Neoplasia Vol. 28. Dahia, PLM and Eng, C (eds). Eng C. (2003). Hum. Mutat., 22, 183–198. Front Horm Res Base: Karger, pp. 50–80. Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Chandrasekharappa SC, Guru SC, Manickam P, Olufemi SE, Gagel R, van Amstel H, Lips C, Nishisho I, Takai S, Collins FS, Emmert-Buck MR, Debelenko LV, Zhuang Z, Marsh D, Robinson B, Frank-Raue K, Raue F, Xue F, Lubensky IA, Liotta LA, Crabtree JS, Wang Y, Roe BA, Noll W, Romei C, Pacini F, Fink M, Niederle B, Zedenius J, Weisemann J, Boguski MS, Agarwal SK, Kester MB, Kim Nordenskjold M, Komminoth P, Hendy G and Mulligan L. YS, Heppner C, Dong Q, Spiegel AM, Burns AL and Marx (1996). JAMA, 2776, 1575–1579. SJ. (1997). Science, 276, 404–407. Eng C, Mulligan LM, Smith DP, Healey CS, Frilling A, Raue Chen F, Kishida T, Yao M, Hustad T, Glavac D, Dean M, F, Neumann HPH, Pfragner R, Behmel A, Lorenzo MJ, Gnarra JR, Orcutt ML, Duh FM, Glenn G, Green J, Hsia Stonehouse TJ, Ponder MA and Ponder BAJ. (1995a). Genes EY, Lamiell J, Li H, Wei MH, Schmidt L, Tory K, Kuzmin Chromosomes Cancer, 12, 209–212. I, Stackhouse T, Latif F, Linehan M, Lerman M and Zbar Eng C, Smith DP, Mulligan LM, Healey CS, Zvelebil MJ, B. (1995). Hum. Mutat., 5, 66–75. Stonehouse TJ, Ponder MA, Jackson CE, Waterfield MD Chen J, Silver WP, Walpita D, Cantor SB, Gazdar AF, and Ponder BAJ. (1995b). Oncogene, 10, 509–513. Tomlinson G, Couch FJ, Weber BL, Ashley T, Livingston Enholm S, Hienonen T, Suomalainen A, Lipton L, DM and Scully R. (1998). Mol. Cell, 2, 317–328. Tomlinson I, Karja V, Eskelinen M, Mecklin J-P, Karhu Chrousos GP and Stratakis CA. (1998). J. Intern. Med., 243, A, Jarvinen H and Aaltonen L. (2003). Am. J. Pathol., 163, 573–579. 827–832. Chung C. (2000). Gastroenterology, 119, 854–865. Entius M, Keller J, Westerman A, van Rees B, van Velthuysen Claus EB, Risch NJ and Thompson WD. (1991). Am. J. Hum. M, de Goeij A, Wilson J, Giardiello F and Offerhaus G. Genet., 48, 232–242. (2001). J. Clin. Pathol., 54, 126–131. Clifford SC, Cockman ME, Smallwood AC, Mole DR, Esteller M, Avizienyte E, Corn P, Lothe R, Baylin S, Aaltonen Woodward ER, Maxwell PH, Ratcliffe PJ and Maher ER. L and Herman J. (2000). Oncogene, 19, 164–168. (2001). Hum. Mol. Genet., 10, 1029–1038. Evans DG, Neuhausen SL, Bulman M, Young K, Gokhale D Coburn M, Pricolo V, DeLuca F and Bland K. (1995). Ann. and Lalloo F. (2004). J. Med. Genet., 41, E21. Surg. Oncol., 2, 386–391. Farndon JR, Leight GS, Dilley WG, Baylin SB, Smallridge Corbetta S, Pizzocaro A, Peracchi M, Beck-Peccoz P, Faglia RC, Harrison TS and Wells SA. (1986). Br. J. Surg., 73, G and Spada A. (1997). Clin. Endocrinol. (Oxford), 47, 278–281. 507–512. Felix CA, Slavc I, Dunn M, Strauss EA, Phillips PC, Rorke Cornelis RS, Neuhausen S, Johannsson O, Arason A, Kelsell LB, Sutton L, Bunin GR and Biegel JA. (1995). Med. D, Ponder BAJ, Tonin P, Hamann U, Lindblom A and Lalle Pediatr. Oncol., 25, 431–436. P. (1995). Genes Chromosomes Cancer, 13, 203–210. Fodde R, Kuipers J, Rosenberg C, Smits R, Kielman M, Dackiw A, Cote G, Fleming J, Schultz P, Stanford P, Gaspar C, van Es J, Breukell C, Wiegant J, Giles R and Vassilopoulou-Sellin R, Evans D, Gagel R and Lee J. Clevers H. (2001). Nat. Cell Biol., 3, 433–438. (1999). Surgery, 126, 1097–1104. Ford D, Easton DF and Peto J. (1995). Am. J. Hum. Genet., Darling TN, Skarulis MC, Steinberg SM, Marx SJ, Spiegel 57, 1457–1462. AM and Turner M. (1997). Arch. Dermatol., 133, 853–857. Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Decker RA, Peacock ML, Borst MJ, Sweet JD and Thompson Devilee P, Bishop DT, Weber B, Lenoir G, Chang-Claude J, NW. (1995). Surgery, 118, 257–264. Sobol H, Teare MD, Streuwing J, Arason A, Scherneck S,

Oncogene Review of 10 highly penetrant cancer syndromes R Nagy et al 6464 Peto J, Rebbeck TR, Tonin P, Neuhausen S, Bardardottir R, Gimm O. (2001). Genetic Disorders of Endocrine Neoplasia, Eyfjord J, Lynch H, Ponder BAJ, Gayther SA, Birch JM, Vol. 28, Dahia PLM and Eng, Charis (eds). Front Horm Res Lindblom A, Stoppa-Lyonnet D, Bignon Y, Borg A, Base: Karger, pp. 103–130. Hamann U, Haites N, Scott RJ, Maugard CM, Vasen H, Gimm O, Marsh DJ, Andrew SD, Frilling A, Dahia PLM, Seitz S, Cannon-Albright LA, Schofield A, Zelada-Hedman Mulligan LM, Zajak JD, Robinson BG and Eng C. (1997). M and Consortium BCL. (1998). Am. J. Hum. Genet., 62, J. Clin. Endocrinol. Metab., 82, 3902–3904. 676–689. Giraud S, Zhang CX, Serova-Sinilnikova OM, Wautot V, Foulkes W, Thiffault I, Gruber S, Horwitz M, Hamel N, Salandre J, Buisson N, Waterlot C, Bauters C, Porchet N, Lee C, Shia J, Markowitz A, Figer A, Friedman E, Aubert J-P, Emy P, Cadiot G, Emperauger B, Cougard P, Farber D, Greenwood C, Bonner J, Nafa K, Walsh T, Goudet P, Sarfati E, Riou JP, Guichard S, Rodier M, Marcus VA, Tornsho L, Gebert J, Marcrae F, Gaff C, Meyrier A, Caron P, Vantyghem M-C, Assayag M, Peix J-L, Bressace-de-Paillerets B, Gregersen P, Weitzel J, Gordon P, Pugeat M, Rohmer V, Valloton M, Lenoir G, Gaudray P, MacNamara E, King M-C, Hampel H, de la Chapelle A, Proye C, Conte-Devolx B, Chanson P, Shugart YY, Goldgar Boyd J, Offit K, Rennert G, Chong H and Ellis N. (2002). D, Murat A and Calender A. (1998). Am. J. Hum. Genet., 63, Am. J. Hum. Genet., 71, 1395–1412. 455–467. Frebourg T, Barbier N, Yan YX, Garber JE, Dreyfus M, Gnarra JR, Tory K, Weng Y, Schmidt L, Wei MH, Li H, Latif Fraumeni Jr JF, Li FP and Friend SH. (1995). Am. J. Hum. F, Liu S, Chen F, Duh F-M, Lubensky I, Duan DR, Genet., 56, 608–615. Florence C, Pozzatti R, Walther MM, Bander NH, Gross- Friedl W, Caspari R, Sengteller M, Uhlhaas S, Lamberti C, man HB, Brauch H, Pomer S, Brooks JD, Isaacs WB, Jungck M, Kadmon M, Wolf M, Fahnenstich J, Gebert J, Lerman MI, Zbar B and Linehan WM. (1994). Nat. Genet., Moslein G, Mangold E and Propping P. (2001). Gut, 48, 7, 85–90. 515–521. Gorlin RJ, Sedano HO, Vickers RA and Cervenka J. (1968). Friedl W, Meuschel S, Caspari R, Lamberti C, Krieger S, Cancer, 22, 293–299. Sengteller M and Propping P. (1996). Hum. Genet., 97, Gorski B, Byrski T, Huzarski T, Jakubowska A, Menkiszak J, 579–584. Gronwald J, Pluzanska A, Bebenek M, Fischer-Maliszewska Friedl W, Uhlhaas S, Schulmann K, Stolte M, Loff S, Back W, L, Grzybowska E, Narod SA and Lubinski J. (2000). Am. J. Mangold E, Stern M, Knaebel H, Sutter C, Weber R, Hum. Genet., 66, 1963–1968. Pistorius S, Burger B and Propping P. (2002). Hum. Genet., Goss K and Groden J. (2000). J. Clin. Oncol., 18, 1967–1979. 111, 108–111. Groden J, Thliveris A, Samowitz W, Carlson M, Gelbert L, Furnari FB, SuHuang H-J and Cavanee WK. (1998). Cancer Albertsen H, Joslyn G, Stevens J, Spirio L, Robertson M, Res., 58, 5002–5008. Sargeant L, Krapcho K, Wolff E, Burt R, Hughes JP, Gao Q, Neuhausen S, Cummings S, Luce M and Olopade OI. Warrington J, McPherson J, Wasmuth J, Le Paslier D, (1997). Am. J. Hum. Genet., 60, 1233–1236. Abderrahim H, Cohen D, Leppert M and White R. (1991). Garber JE, Goldstein AM, Kantor AF, Dreyfus MG, Cell, 66, 589–600. Fraumeni Jr JF and Li FP. (1991). Cancer Res., 51, Gross A, McDonnell J and Korsmeyer S. (1999). Genes Dev., 6094–6097. 13, 1899–1911. Gardner E, Papi L, Easton DF, Cummings T, Jackson CE, Gruber S, Entius M, Petersen G, Laken S, Longo P, Boyer R, Kaplan M, Love DR, Mole SE, Moore JK, Mulligan LM, Levin A, Mujumdar U, Trent J, Kinzler K, Vogelstein B, Norum RA, Ponder MA, Reichlin S, Stall G, Telenius H, Hamilton S, Polymeropoulos M, Offerhaus G and Giardiel- Telenius-Berg M and Ponder BAJ. (1993). Hum. Mol. lo F. (1998). Cancer Res., 58, 5267–5270. Genet., 2, 241–246. Guillem J, Smith A, Calle J and Ruo L. (1999). Curr. Probl. Gardner E and Richards R. (1953). Am. J. Hum. Genet., 5, Surg., 36, 217–323. 139–147. Ha˚ kansson S, Johansson O, Johansson U, Sellberg G, Loman Gayther SA, Harrington P, Russell P, Kharkevich G, N, Gerdes A-M, Holmberg E, Dahl N, Pandis N, Garkavtseva RF and Ponder BA. (1997a). Am. J. Hum. Kristofferson U, Olsson H and Borg A. (1997). Am. J. Genet., 60, 1239–1242. Hum. Genet., 60, 1068–1078. Gayther SA, Mangion J, Russell P, Seal S, Barfoot R, Halford S, Rowan A, Lipton L, Sieber O, Pack K, Thomas Ponder BAJ, Stratton MR and Easton D. (1997b). Nat. HJW, Hodgson S, Bodmer W and Tomlinson G. (2003). Genet., 15, 103–105. Am. J. Pathol., 162, 1545–1548. Gayther SA, Warren W, Mazoyer S, Russell PA, Harrington Hartley AL, Birch JM, Tricker KJ, Wallace SA, Kelsey AM, PA, Chiano M, Seal S, Hamoudi R, van Rensburg EJ, Harris M and Morris Jones PH. (1993). Cancer Genet. Dunning AM, Love R, Evans G, Easton D, Clayton D, Cytogenet., 67, 133–135. Stratton MR and Ponder BAJ. (1995). Nat. Genet., 11, He L, Yu JX, Liu L, Buyse IM, Wang MS, Yang QC, 428–433. Nakagawara A, Brodeur GM, Shi YE and Huang S. (1998). Giardiello F, Offerhaus G, Krush A, Tersmette A, Booker S, Cancer Res., 58, 4238–4244. Kelley N and Hamilton S. (1993). Gut, 34, 1394–1396. Heiskanen I, Kellokumpu I and Jarvinen H. (1999). Endo- Giardiello F, Petersen G, Brensigner J, Luce M, Cayouetter scopy, 31, 412–416. M, Bacon J, Booker S and Hamilton SR. (1996). Gut, 39, Helwig E. (1946). Am. J. Dis. Child., 72, 289–295. 867–869. Hemminki A, Markie D, Tomlinson I, Avizienyte E, Roth S, Giardiello FM, Welsh S, Hamilton SR, Offerhaus G, Loukola A, Bignell G, Warren W, Aminoff M, Hoglund P, Gittelsohn A, Booker S, Krush A, Yardley J and Luk G. Jarvinen H, Kristo P, Pelin K, Ridanpaa M, Salovaara R, (1987). N. Engl. J. Med., 316, 1511–1514. Toro T, Bodmer W, Olschwang S, Olsen A, Stratton M, Gille J, Hogervorst F, Pals G, Wijnen J, van Schooten R, de la Chapelle A and Aaltonen L. (1998). Nature, 391, Dommering C, Meijer G, Craanen M, Nederlof P, de Jong 184–187. D, McElgunn C, Schouten J and Menko F. (2002). Br. J. Hemminki A, Tomlinson I, Markie D, Jarvinen H, Sistonen P, Cancer, 87, 892–897. Bjorkqvist A, Knuutila S, Salovaara R, Bodmer W, Shibata

Oncogene Review of 10 highly penetrant cancer syndromes R Nagy et al 6465 D, de la Chapelle A and Aaltonen L. (1997). Nat. Genet., 15, Karuman P, Gozani O, Odze R, Zhou X, Zhu H, Shaw R, 87–90. Brien T, Bozzuto C, Ooi D, Cantley L and Yuan J. (2001). Hisada M, Garber JE, Fung CY, Fraumeni Jr JF and Li FP. Mol. Cell, 7, 1307–1319. (1998). J. Natl. Cancer Inst., 90, 606–610. Kinzler K, Nilbert M, Su L, Vogelstein B, Bryan T, Levy D, Hoffman MA, Ohh M, Yang H, Klco JM, Ivan M Smith K, Preisinger A, Hedge P and McKechnie D. (1991). and Kaelin Jr WG. (2001). Hum. Mol. Genet., 10, Science, 253, 661–665. 1019–1027. Klein RD, Sherman D, Ho W-H, Stone D, Bennett GL, Hopper JL, Southey MC, Dite GS, Jolley DJ, Giles GG, Moffat B, Vandlen R, Simmons L, Gu Q, Hongo J-A, McCredie MRE, Easton D, Venter DJ and Study ABC. Devaux B, Poulsen K, Armanini M, Nozaki C, Asai N, (1999). Cancer Epidemiol. Biomarkers Prev., 8, 741–747. Goddard A, Phillips H, Henderson CE, Takahashi M and Horrielleno E, Eckert C and Ackerman L. (1957). Cancer, 10, Rosenthal A. (1997). Nature, 387, 717–721. 1210–1215. Kolodner RD, Tytell J and Schmeits J. (1999). Cancer Res., 59, Howe J, Bair J, Sayed M, Anderson M, Mitros F, Petersen G, 5068–5074. Velculescu V, Traverso G and Vogelstein B. (2001). Nat. Korinek V, Barker N, Morin P, van Wichen D, de Weger R, Genet., 28, 184–187. Kinzler K, Vogelstein B and Clevers H. (1997). Science, 275, Howe J, Roth S, Ringold J, Summers R, Jarvinen H, 1784–1787. Sistonen P, Tomlinson I, Houlston R, Bevan S, Mitros Kotzbauer PT, Lampe PA, Heuckeroth RO, Golden JP, F, Stone E and Aaltonen L. (1998). Science, 280, Creedon DJ, Johnson EM and Milbrandt J. (1996). Nature, 1086–1088. 384, 467–470. Howlett NG, Taniguchi T, Olson S, Cox B, Waisfisz Q, Kretzchmar M. (2000). Breast Cancer Res., 2, 107–115. de Die-Smulders C, Persky N, Grompe M, Joenje H, Pals G, Kuismanen SA, Moisio AL, Schweizer P, Truninger K, Ikeda H, Fox E and D’Andrea AD. (2002). Science, 297, Salovaara R, Arola J, Butzow R, Jiricny J, Nystrom- 606–609. Lahti M and Peltomaki P. (2002). Am. J. Pathol., 160, Hutter P, Couturier A, Scott R, Alday P, Delozier-Blanchet C, 1953–1958. Cachat F, Antonarakis S, Joris F, Gaudin M, D’Amato L Laken SJ, Petersen GM, Gruber SB, Oddoux C, Ostrer H, and Buerstedde J. (1996). J. Med. Genet., 33, 636–640. Giardiello FM, Hamilton SR, Hampel H, Markowitz A, Hwang S-J, Lozano G, Amos CI and Strong LC. (2003). Am. Klimstra D, Jhanwar S, Winawer S, Offit K, Luce MC, J. Hum. Genet., 72, 975–983. Kinzler KW and Vogelstein B. (1997). Nat. Genet., 17, Iliopoulos O, Levy AP, Jiang C, Kaelin Jr WG and 79–83. Goldberg MA. (1996). Proc. Natl. Acad. Sci. USA, 93, Lalloo F, Varley JM, Ellis D, Moran A, O’Dair L, Pharaoh P, 10595–10599. Evans DGR and the Early Onset Breast Cancer Study Iliopoulos O, Ohh M and Kaelin Jr WG. (1998). Proc. Natl. Group. (2003). Lancet, 361, 1101–1102. Acad. Sci. USA, 95, 11661–11666. Lamiell JM, Salazar FG and Hsia YE. (1989). Medicine Inoki K, Zhu T and Guan KL. (2003). Cell, 115, 577–590. (Baltimore), 68, 1–29. Ito S, Iwashita T, Asai N, Murakami H, Iwata Y, Larsson C, Skosgeid B, O¨berg K, Nakamura Y and Sobue G and Takahashi M. (1997). Cancer Res., 57, Nordenskjo¨ld M. (1988). Nature, 332, 85–87. 2870–2872. Latif F, Tory K, Gnarra J, Yao M, Duh F-M, Orcutt M-L, Jacoby R, Schlack S, Cole C, Skarbek M, Harris C and Stackhouse T, Kuzmin I, Modi W, Geil L, Schmidt L, Zhou Meisner L. (1997). Gastroenterology, 112, 1398–1403. F, Weng Y, Duan DR, Dean M, Glavac D, Richards FM, Jarvinen H. (1992). Gut, 33, 357–360. Crossey PA, Ferguson-Smith MA, Le Paslier D, Chumakov Jarvinen H and Franssila K. (1984). Gut, 25, 792–795. I, Cohen D, Chinault CA, Maher ER, Linehan WM, Zbar B Jasin M. (2002). Oncogene, 21, 8981–8993. and Lerman MI. (1993). Science, 260, 1317–1320. Jass JR, Williams CB, Bussey HJR and Morson B. (1988). Levy AP, Levy NS and Goldberg MA. (1996). J. Biol. Chem., Histopathology, 13, 619–630. 271, 25492–25497. Jeghers H, McKusick V and Katz K. (1949). N. Engl. J. Med., Li D-M and Sun H. (1997). Cancer Res., 57, 2124–2129. 241, 993–1005. Li FP and Fraumeni Jr JF. (1969). Ann. Intern. Med., 71, Jiang G, Liu L, Buyse IM, Simon D and Huang S. (1999). Int. 747–752. J. Cancer, 83, 541–546. Li FP, Fraumeni Jr JF, Mulvihill JJ, Blattner WA, Dreyfus Jiang GL and Huang S. (2000). Histol. Histopathol., 15, MG, Tucker MA and Miller RW. (1988). Cancer Res., 51, 109–117. 6094–6097. Jing S, Wen D, Yu Y, Holst PL, Luo Y, Fang M, Tamir R, Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang S, Puc J, Antonio L, Hu Z, Cupples R, Louis J-C, Hu S, Altrock BW Miliaresis C, Rodgers L, McCombie R, Bigner SH, and Fox GM. (1996). Cell, 85, 1113–1124. Giovanella BC, Ittman M, Tycko B, Hibshoosh H, Wigler Johannsson O, Ostermeyer EA, Hakansson S, Friedman LS, MH and Parsons R. (1997). Science, 275, 1943–1947. Johansson U, Sellberg G, Brondum-Nielsen K, Sele V, Li YJ, Sanson M, Hoang-Xuan K, Delattre JY, Poisson M, Olsson H, King MC and Borg A. (1996). Am. J. Hum. Thomas G and Hamelin R. (1995). Int. J. Cancer, 64, Genet., 58, 441–450. 383–387. Jones S, Emmerson P, Maynard J, Best J, Jordan S, Williams Liaw D, Marsh DJ, Li J, Dahia PLM, Wang SI, Zheng Z, Bose GH, Sampson J and Cheadle JP. (2002). Hum. Mol. Genet., S, Call KM, Tsou HC, Peacocke M, Eng C and Parsons R. 11, 2961–2967. (1997). Nat. Genet., 16, 64–67. Kadmon M, Tandara A and Herfarth C. (2001). Int. J. Liede A, Cohen B, Black DM, Davidson RH, Renwick A, Colorectal Dis., 16, 63–75. Hoodfar E, Olopade OI, Micek M, Anderson V, De Mey R, Kaelin WG and Maher ER. (1998). Trends Genet., 14, Fordyce A, Warner E, Dann JL, King MC, Weber B, Narod 423–426. SA and Steel CM. (2000). Br. J. Cancer, 82, 705–711. Kaplan KB, Burds AA, Swedlow JR, Bekir SS, Sorger PK and Lipton L, Halford S, Johnson V, Novelli M, Jones A, Nathke IS. (2001). Nat. Cell Biol., 3, 429–432. Cummings C, Barclay E, Sieber O, Sadat A, Bisgaard ML,

Oncogene Review of 10 highly penetrant cancer syndromes R Nagy et al 6466 Hodgson SV, Aaltonen L, Thomas HJW and Tomlinson Massague J. (2000). Nat. Rev. Mol. Cell Biol., 1, 169–178. IPM. (2003). Cancer Res., 63, 7595–7599. Mathew CGP, Chin KS, Easton DF, Thorpe K, Carter C, Longy M and Lacombe D. (1996). Ann. Genet., 39, 35–42. Liou GI, Fong S-L, Bridges CDB, Haak H, Nieuwenhuijzen Lynch H, Boman B, Watson P, Lynch P, Bufo P and Krusman AC, Schifter S, Hansen HH, Telenius H, MIngazzini P. (1988). Gastroenterol. Clin. N. Am., 17, Telenius-Berg M and Ponder BAJ. (1987). Nature, 328, 679–711. 527–528. Lynch H and Krush A. (1971). Cancer, 27, 1505–1511. Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux Lynch HT, Coronel SM, Okimoto R, Hampel H, Sweet K, EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER and Lynch JF, Barrows A, Wijnen J, van der Klift H, Franken P, Ratcliffe PJ. (1999). Nature, 399, 271–275. Wagner A, Fodde R and de la Chapelle A. (2004). JAMA, McColl I, Bussey H and Veale A. (1964). Proc. R. Soc. Med., 291, 718–724. 57, 896–899. Lynch HT and de la Chapelle A. (2003). N. Engl. J. Med., 348, McIntyre JF, Smith-Sorensen B, Friend SH, Kassell J, 919–932. Borresen-Dale AL, Yan YX, Russo C, Sato J, Barbier N, Lynch HT, Mulcahy GM, Harris RE, Guirgis HA and Lynch Miser J, Malkin D and Gebhardt MC. (1994). J. Clin. JF. (1978). Cancer (Philadelphia), 41, 2055–2064. Oncol., 12, 925–930. Lynch HT and Smyrk T. (1996). Gastroenterology, 110, Megerian CA, McKenna MJ, Nuss RC, Maniglia AJ, 943–954. Ojemann RG, Pilch BZ and Nadol JBJ. (1995). Laryngo- Maddock IR, Moran A, Maher EA, Teare MD, Norman A, scope, 105, 801–808. Payne SJ, Whitehouse R, Dodd C, Lavin M, Hartley N, Meijers-Heijboer H, Wijnen J, Vasen H, Wasielewski M, Super M and Evans DGR. (1996). J. Med. Genet., 33, 120–127. Wagner A, Hollestelle A, Elstrodt F, van den Bos R, de Maehama T and Dixon JE. (1998). J. Biol. Chem., 273, Snoo A, Tjon A Fat G, Brekelmans C, Jagmohan S, 13375–13378. Franken P, Verkuijlen P, van den Ouweland A, Chapman P, Maher ER, Iselius L, Yates JRW, Littler M, Benjamin C, Tops C, Moslein G, Burn J, Lynch H, Klijn J, Fodde R and Harris R, Sampson J, Williams A, Ferguson-Smith MA and Schutte M. (2003). Am. J. Hum. Genet., 72, 1308–1314. Morton N. (1991). J. Med. Genet., 28, 443–447. Miedlich S, Lohmann T, Schneyer U, Lamesch P and Paschke Maher ER and Kaelin WG. (1997). Medicine (Baltimore), 76, R. (2001). Eur. J. Endocrinol., 145, 155–160. 381–391. Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harsh- Maher ER, Yates JR, Harries R, Benjamin C, Harris R, man K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding Moore AT and Ferguson-Smith MA. (1990). Q. J. Med., 77, W, Bell R, Rosenthal J, Hussey C, Tran T, McClure M, Frye 1151–1163. C, Hattier T, Phelps R, Haugen-Strano A, Katcher H, Malkin D, Jolly K, Barbier N, Look A, Friend S, Gebhardt M, Yakumo K, Gholami Z, Shaffer D, Stone S, Bayer S, Wray Andersen T, Borresen A, Li F, Garber J and Strong LC. C, Bogden R, Dayananth P, Ward J, Tonin P, Narod S, (1992). N. Engl. J. Med., 326, 1309–1315. Bristow PK, Norris FH, Helvering L, Morrison P, Rosteck Malkin D, Li FP, Fraumeni Jr JF, Strong LC, Nelson CE, P, Lai M, Barrett JC, Lewis C, Neuhausen S, Cannon- Kim DH, Kassel J, Gryka MA, Bischoff FZ, Tainsky MA Albright L, Goldgar D, Wiseman R, Kamb A and Skolnick and Friend SH. (1990). Science, 250, 1233–1238. MH. (1994). Science, 266, 66–71. Manning BD, Tee AR, Logsdon MN, Blenis J and Cantley Millar A, Pal T, Madlensky L, Sherman C, Temple L, Mitri A, LC. (2002). Mol. Cell, 10, 151–162. Cheng H, Marcus V, Gallinger S, Redston M, Bapat B and Markowitz S, Wang J, Myeroff L, Parsons R, Sun L, Narod S. (1999). Hum. Mol. Genet., 8, 823–829. Lutterbaugh J, Fan RS, Zborowska E, Kinzler K, Vogel- Miyaki M, Iijima T, Hosono K, Ishii R, Yasuno M, Mori T, stein B, Brattain M and Willson JKV. (1995). Science, 268, Toi M, Hishima T, Shitara N, Tamura K, Utsunomiya J, 1336–1338. Kobayashi N, Kuroki T and Iwama T. (2000). Cancer Res., Marra G and Jiricny J. (2003). N. Engl. J. Med., 348, 845. 60, 6311–6313. Marsh DJ, Coulon V, Lunetta KL, Rocca-Serra P, Dahia Miyauchi A, Futami H, Hai N, Yokozawa T, Kuma K, Aoki PLM, Zheng Z, Liaw D, Caron S, Duboue´ B, Lin AY, N, Kosugi S, Sugano K and Yamaguchi K. (1999). Jpn. J. Richardson A-L, Bonnetblanc J-M, Bressieux J-M, Cabar- Cancer Res., 90, 1–5. rot-Moreau A, Chompret A, Demange L, Eeles R, Yahanda Moisio A, Jarvinen H and Peltomaki P. (2002). Gut, 50, AM, Fearon ER, Fricker J-P, Gorlin RJ, Hodgson SV, 845–850. Huson S, Lacombe D, LePrat F, Odent S, Toulouse C, Mulligan LM, Eng C, Attie´ T, Lyonnet S, Marsh DJ, Hyland Olopade OI, Sobol H, Tishler S, Woods CG, Robinson BG, VJ, Robinson BG, Frilling A, Verellen-Dumoulin C, Safar Weber HC, Parsons R, Peacocke M, Longy M and Eng C. A, Venter DJ, Munnich A and Ponder BAJ. (1994a). Hum. (1998). Hum. Mol. Genet., 7, 507–515. Mol. Genet., 3, 2163–2167. Marsh DJ, Dahia PLM, Zheng Z, Liaw D, Parsons R, Gorlin Mulligan LM, Eng C, Healey CS, Clayton D, Kwok JBJ, RJ and Eng C. (1997). Nat. Genet., 16, 333–334. Gardner E, Ponder MA, Frilling A, Jackson CE, Lehnert H, Marsh DJ, Kum JB, Lunetta KL, Bennett MJ, Gorlin RJ, Neumann HPH, Thibodeau SN and Ponder BAJ. (1994b). Ahmed SF, Bodurtha J, Crowe C, Curtis MA, Dazouki M, Nat. Genet., 6, 70–74. Dunn T, Feit H, Geraghty MT, Graham JM, Hodgson SV, Mulligan LM, Gardner E, Smith BA, Mathew CGP and Hunter A, Korf BR, Manchester D, Miesfeldt S, Murday Ponder BAJ. (1993). Genes Chromosomes Cancer, 6, VA, Nathanson KA, Parisi M, Pober B, Romano C, Tolmie 166–177. JL, Trembath R, Winter RM, Zackai EH, Zori RT, Weng Murphy GP, Lawrence WR and Lenhard RE. (1995). LP, Dahia PLM and Eng C. (1999). Hum. Mol. Genet., 8, American Cancer Society Textbook of Clinical Oncology 1461–1472. 2nd edn. American Cancer Society: Atlanta, GA. Marx S. (2000). N. Engl. J. Med., 343, 1863–1875. Myers MP, Pass I, Batty IH, van der Kaay J, Storalov Marx SJ. (2002). The Genetic Basis of Human Cancer JP, Hemmings BA, Wigler MH, Downes CP and Vogelstein B, Kinzler KW (eds). McGraw Hill: New York, Tonks NK. (1998). Proc. Natl. Acad. Sci. USA, 95, NY, pp. 475–499. 13513–13518.

Oncogene Review of 10 highly penetrant cancer syndromes R Nagy et al 6467 Myers MP, Stolarov J, Eng C, Li J, Wang SI, Wigler MH, Flinter F, Maidment CGH, Trembath R and Thakker RV. Parsons R and Tonks NK. (1997). Proc. Natl. Acad. Sci. (2003). Clin. Endocrinol., 58, 639–646. USA, 94, 9052–9057. Parc Y, Boisson C, Thomas G and Olschwang S. (2003). Nakagawa H, Tyan H and Lockman J. (2002). Cancer Res., J. Med. Genet., 40, 208–213. 62, 4579–4582. Park Y, Sin K-H and Park J-G. (2000). Clin. Cancer Res., 6, Nakamura T, Ishizaka Y, Nagao M, Hara M and Ishikawa T. 2994–2998. (1994). J. Pathol., 172, 255–260. Pasini B, Hofstra R, Yin L, Bocciardi R, Santanaria G, Nelen MR, Kremer H, Konings IBM, Schoute F, van Essen Grootscholten P, Ceccherini I, Patrone G, Priolo M, Buys C AJ, Koch R, Woods CG, Fryns J-P, Hamel B, Hoefsloot and Romeo G. (1995). Oncogene, 11, 1737–1743. LH, Peeters EAJ and Padberg GW. (1999). Eur. J. Hum. Pause A, Lee S, Lonergan KM and Klausner RD. (1998). Genet., 7, 267–273. Proc. Natl. Acad. Sci. USA, 95, 993–998. Nelen MR, Padberg GW, Peeters EAJ, Lin AY, van den Helm Peelen T, van Vliet M, Petrij-Bosch A, Mieremet R, Czabo C, B, Frants RR, Coulon V, Goldstein AM, van Reen MMM, van den Ouweland AMW, Hogervorst F, Brohet R, Easton DF, Eeles RA, Hodgson S, Mulvihill JJ, Murday Ligtenberg MJL, Teugels E, van der Luijt R, van der Hout VA, Tucker MA, Mariman ECM, Starink TM, Ponder BAJ, AH, Gille JJP, Pals G, Jedema I, Olmer R, van Leeuwen I, Ropers HH, Kremer H, Longy M and Eng C. (1996). Nat. Newman B, Plandsoen M, van der Est M, Brink G, Genet., 13, 114–116. Hageman S, Arts PJW, Bakker MM, Willems HW, Nelen MR, van Staveren CG, Peeters EAJ, Ben Hassel M, van der Looij E, Neyns B, Bonduelle M, Jansen R, Gorlin RJ, Hamm H, Lindboe CF, Fryns J-P, Sijmons RH, Oosterwijk JC, Sijmons R, Smeets HJM, van Asperen CJ, Woods DG, Mariman ECM, Padberg GW and Kremer H. Meijers-Heijboer H, Klijn JGM, de Greve J, King M-C, (1997). Hum. Mol. Genet., 6, 1383–1387. Menki FH, Brunner HG, Halley D, van Ommen G-J, Neuhausen S, Gilewski T, Norton L, Tran T, McGuire P, Vasen HFA, Cornelisse CJ, van’t Veer LJ, de Knijff P, Swensen J, Hampel H, Borgen P, Brown K, Skolnick M, Bakker E and Devilee P. (1997). Am. J. Hum. Genet., 60, Shattuch-Eidens D, Jhanwar S, Goldgar D and Offit K. 1041–1049. (1996). Nat. Genet., 13, 126–128. Petrij-Bosch A, Peelen T, van Vliet M, van Eijk R, Olmer R, Neumann HPH. (1987). J. Vasc. Dis., 16, 220–226. Drusedau M, Hogervorst FB, Hageman S, Arts PJ, Neumann HPH, Brauch B, McWhinney SR, Bender BU, Ligtenberg MJ, Meijers-Heijboer H, Klijn JG, Vasen HF, Gimm O, Franke G, Schipper J, Klisch J, Alteho¨her C, Cornelisse CJ, van’t Veer LJ, Bakker E, van Ommen GJ and Zerres K, Januszewicz A and Eng C. (2002). N. Engl. J. Devilee P. (1997). Nat. Genet., 17, 341–345. Med., 346, 1459–1466. Peutz JLA. (1921). Nederl. Maandschr. Geneesk., 10, 134–146. Neumann HPH and Wiestler OD. (1991). Lancet, 337, Piao Z, Fang W, Malkhosyan S, Kim H, Horii A, Perucho M 1052–1054. and Huang S. (2000). Cancer Res., 60, 4701–4704. Nichols KE, Malkin D, Garber JE, Fraumeni Jr JF and Li FP. Pipeleers-Marichal M, Somers G, Willems G, Foulis A, Imrie (2001). Cancer Epidemiol. Biomarkers Prev., 10, 83–87. C, Bishop A, Polak J, Hacki W, Stamm B, Heitz P and Nilsson O, Tissell L-E, Jansson S, Ahlman H, Gimm O and Klo¨ppel G. (1990). N. Engl. J. Med., 322, 723–727. Eng C. (1999). JAMA, 281, 1587–1588. Poisson A, Zablewska B and Gaudray P. (2003). Cancer Lett., Nishisho I, Nakamura Y, Miyoshi Y, Miki Y, Ando H, Horii 189, 1–10. A, Koyama K, Utsunomiya J, Baba S and Hedge P. (1991). Ponder BAJ, Ponder MA, Coffey R, Pembrey M, Gagel RF, Science, 253, 665–669. Telenius-Berg M, Semple P and Easton DF. (1988). Lancet, Norton JA, Fraker DL, Alexander HR, Venzon DJ, Doppman i, 397–400. JL, Serrano J, Goebel SU, Peghini PL, Roy PK, Gibril F Ribeiro RC, Sandrini F, Figueiredo B, Zambetti GP, and Jensen RT. (1999). N. Engl. J. Med., 341, 635–644. Michalkiewicz E, Lafferty AR, DeLacerda L, Rabin M, Nystrom-Lahti M, Kristo P, Nicolaides N, Chang S, Aaltonen Cadwell C, Sampaio G, Cat I, Stratakis CA and Sandrini R. L, Moisio A, Jarvinen H, Mecklin J-P, Kinzler K, Vogelstein (2001). Proc. Natl. Acad. Sci. USA, 98, 9330–9335. B and de la Chapelle A. (1995). Nat. Med., 1, 1203–1206. Roa BB, Boyd AA, Volcik K and Richards CS. (1996). Nat. Offit K, Gilewski T, McGuire P, Schluger A, Hampel H, Genet., 14, 185–187. Brown K, Swensen J, Neuhausen S, Skolnick M, Norton L Roth S and Helwig E. (1963). Cancer, 16, 468–472. and Goldgar D. (1996). Lancet, 347, 1643–1645. Rotter V, Aloni-Grinstein R, Schwartz D, Elkind NB, Simons Ohh M, Yauch RL, Lonergan KM, Whaley JM, Stemmer- A, Wolkowicz R, Lavigne M, Beserman P, Kapon A and Rachamimov AC, Louis DN, Gavin BJ, Kley N, Kaelin WG Goldfinger N. (1994). Semin. Cancer Biol., 5, 229–236. and Iliopoulos O. (1998). Mol. Cell, 1, 959–968. Roy PK, Venzon DJ, Shojamanesh H, Abou-Saif A, Peghini Olivier M, Goldgar DE, Sodha N, Ohgaki H, Kleihues P, P, Doppman JL, Gibril F and Jensen RT. (2000). Medicine Hainaut P and Eeles RA. (2003). Cancer Res., 63, (Baltimore), 79, 379–411. 6643–6650. Rubinfeld B, Souza B, Albert I, Muller O, Chamberlain S, Olschwang S, Markie D, Seal S, Neale K, Phillips R, Cottrell Masiarz F, Munemitsu S and Polakis P. (1993). Science, 262, S, Ellis I, Hodgson S, Zauber P, Spigelman A, Iwama T, 1731–1734. Loff S, McKeown C, Marchese C, Sampson J, Davies S, Sakurada K, Furukawa T, Kato Y, Kayama T, Huang S and Talbot I, Wyke J, Thomas G, Bodmer W, Hemminki A, Horii A. (2001). Genes Chromosomes Cancer, 30, 207–211. Avizienyte E, de la Chapelle A, Aaltonen L and Tomlinson Salovaara R, Loukola A, Kristo P, Kaariainen H, Ahtola H, I. (1998). J. Med. Genet., 35, 42–44. Eskelinen M, Harkonen N, Julkunen R, Kangas E, Ojala S, Olschwang S, Tiret A, Laurent-Puig P, Muleris M, Parc R and Tulikoura J, Valkamo E, Jarvinen H, Mecklin J-P, Aaltonen Thomas G. (1993). Cell, 75, 959–968. LA and de la Chapelle A. (2000). J. Clin. Oncol., 18, Pachnis V, Mankoo B and Costantini F. (1993). Development, 2193–2200. 119, 1005–1017. Sampson J, Dolwani S, Jones S, Eccles D, Ellis A, Evans D, Pannett AAJ, Kennedy AM, Turner JJO, Forbes SA, Cavaco Frayling I, Jordan S, Maher E, Mak T, Maynard J, BM, Bassett JHD, Cianferotti L, Harding B, Shine B, Pigatto F, Shaw J and Cheadle J. (2003). Lancet, 362, 39–41.

Oncogene Review of 10 highly penetrant cancer syndromes R Nagy et al 6468 Sankila R, Aaltonen LA, Jarvinen H and Mecklin J-P. (1996). Sodha N, Houlston RS, Bullock S, Yuille MA, Chu C, Gastroenterology, 110, 682–687. Turner G and Eeles RA. (2002). Hum. Mutat., 20, Santoro M, Carlomagno F, Romano A, Bottaro DP, Dathan 460–462. NA, Grieco M, Fusco A, Vecchio G, Matoskova B, Kraus Soloman C and Burt R. In: GeneReviews at Gene MH and Di Fiore PP. (1995). Science, 267, 381–383. Tests: Medical Information Resource (database online). Sayed M, Ahmed A, Ringold J, Anderson M, Bair J, Mitros F, Copyright, University of Washington: Seattle, 1997–2004. Lynch H, Tinley S, Petersen G, Giardiello F, Vogelstein B Available at http://www.genetests.org (Updated 15 March and Howe J. (2002). Ann. Surg. Oncol., 9, 901–906. 2004). Scheithauer BW, Laws ERJ, Kovacs K, Horvath E, Randall Somasundaram K. (2003). J. Cell. Biochem., 88, 1084–1091. RV and Carney JA. (1987). Semin. Diagn. Pathol., 4, Songyang Z, Carraway III KL, Eck MJ, Harrison SC, 205–211. Feldman RA, Mohammadi M, Schlessinger J, Hubbard Schnepp RW, Mao H, Sykes SM, Zong WX, Silva A, La P and SR, Smith DP, Eng C, Lorenzo MJ, Ponder BAJ, Mayer BJ Hua X. (2003). J. Biol. Chem., 279, 10685–10691. and Cantley LC. (1995). Nature, 373, 536–539. Schoenfeld A, Davidowitz EJ and Burk RD. (1998). Proc. Soravia C, Berk T, Madlensky L, Mitri A, Cheng H, Gallinger Natl. Acad. Sci. USA, 95, 8817–8822. S, Cohen Z and Bapat BV. (1998). Am. J. Hum. Genet., 62, Schuffenecker I, Ginet N, Goldgar D, Eng C, Chambe 1290–1301. B, Boneu A, Houdent C, Pallo D, Schlumberger M, Spirio L, Olschwang S, Groden J, Robertson M, Samowitz W, Thivolet C and Lenoir GM. (1997). Am. J. Hum. Genet., Joslyn G, Gelbert L, Thliveris A, Carlson M and Otterud B. 60, 233–237. (1993). Cell, 75, 951–957. Schuffenecker I, Virally-Monod M, Brohet R, Goldgar D, Srivastava S, Zou Z, Pirollo K, Blattner W and Chang EH. Conte-Devolx B, Leclerc L, Chabre O, Boneu A, Caron J, (1990). Nature, 348, 747–749. Houdent C, Modigliani E, Rohmer V, Schlumberger M, Eng Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, C, Guillausseau PJ and Lenoir GM. (1998). J. Clin. Mirtsos C, Sasaki T, Rulland J, Penninger JM, Siderovski Endocrinol. Metab., 83, 487–491. DP and Mak TW. (1998). Cell, 95, 1–20. Schutte M, Seal S, Barfoot R, Meijers-Heijboer H, Wasie- Starink TM, van der Veen JPW, Arwert F, de Waal LP, lewski M, Evans G, Eccles D, Meijers C, Lohman F, Klijn J, de Lange GG, Gille JJP and Eriksson AW. (1986). Clin. Ouweland A, The Breast Cancer Linkage Consortium, Genet., 29, 222–233. Futreal PA, Nathanson KL, Weber BL, Easton DF, Steck PA, Pershouse MA, Jasser SA, Yung WKA, Lin H, Stratton MR and Rahman N. (2003). Am. J. Hum. Genet., Ligon AH, Langford LA, Baumgard ML, Hattier T, 72, 1023–1028. Davis T, Frye C, Hu R, Swedlund B, Teng DHF and Scully R, Anderson SF, Chao DM, Wei W, Ye L, Young RA, Tavtigian SV. (1997). Nat. Genet., 15, 356–362. Livingston DM and Parvin JD. (1997a). Proc. Natl. Acad. Stolle C, Glenn G, Zbar B, Humphreys JS, Choyke P, Sci. USA, 94, 5605–5610. Walther M, Pack S, Hurley K, Andrey C, Klausner R and Scully R, Chen J, Plug A, Xiao Y, Weaver D, Feunteun J, Linehan WM. (1998). Hum. Mutat., 12, 417–423. Ashley T and Livingston DM. (1997b). Cell, 88, 265–275. Strong LC, Stine M and Norsted TL. (1987). J. Natl. Cancer Shannon K, Gimm O, Hinze R, Dralle E and Eng C. (1999). Inst., 79, 1213–1220. J. Endocr. Genet., 1, 39–45. Struewing JP, Abeliovich D, Peretz T, Avishai N, Shepard N, Bussey H and Jass J. (1987). Am. J. Surg. Pathol., Kaback MM, Collins FS and Brody LC. (1995). Nat. 11, 743–749. Genet., 11, 198–2000. Sidransky D, Tokino T, Helzlsouer K, Zehnbauer B, Rausch Struewing JP, Hartge P, Wacholder S, Baker SM, Berlin M, G, Shelton B, Prestigiacomo L, Vogelstein B and Davidson McAdams M, Timmerman MM, Brody LC and Tucker N. (1992). Cancer Res., 52, 2984–2986. MA. (1997). N. Engl. J. Med., 336, 1401–1408. Sieber O, Lipton L, Crabtree M, Heinimann K, Fidalgo P, Syngal S, Fox EA, Eng C, Kolodner RD and Garber JE. Phillips R, Bisgaard M, Orntoft T, Aaltonen L, Hodgson S, (2000). J. Med. Genet., 37, 641–645. Thomas H and Tomlinson I. (2003). N. Engl. J. Med., 348, Takahashi M, Buma Y, Iwamoto T, Inaguma Y, Ikeda H and 791–799. Hiai H. (1988). Oncogene, 3, 571–578. Simard J, Tonin P, Durocher F, Morgan K, Rommens J, Takahashi M and Cooper GM. (1987). Mol. Cell. Biol., 3, Gingras S, Samson C, Leblanc JF, Belanger C, Dion F, Liu 1378–1385. Q, Skolnick M, Goldgar D, Shattuck-Eidens D, Labrie F Takahashi M, Ritz J and Cooper G. (1985). Cell, 42, and Narod SA. (1994). Nat. Genet., 8, 392–398. 581–588. Simpson NE, Kidd KK, Goodfellow PJ, McDermid H, Myers Teh B, Farnebo F, Kristoffersson U, Sundelin B, Cardinal J, S, Kidd JR, Jackson CE, Duncan AMV, Farrer LA, Brasch Axelson R, Yap A, Epstein M, Heath H, Cameron D K, Castiglione C, Genel M, Gertner J, Greenberg CR, and Larsson C. (1996). J. Clin. Endocrinol. Metab., 81, Gusella JF, Holden JJ and White BN. (1987). Nature, 328, 4204–4211. 528–530. Teh BT, Zedenius J, Kytola S, Skogseid B, Trotter J, Choplin Skogseid B, Larsson C, Lindgren P, Kvanta E, Rastad J, H, Twigg S, Farnebo F, Giraud S, Cameron D, Robinson Theodorsson E, Wide L, Wilander E and Oberg K. (1992). BG, Calender A, Larsson C and Salmela P. (1998). Ann. J. Clin. Endocrinol. Metab., 75, 76–81. Surg., 228, 99–105. Skosgeid B, Rastad J and O¨berg K. (1994). Endocrinol. Metab. Thakker RV. (1995). Endocrinology DeGroot LJ, Besser GK, Clin. N. Am., 23, 1–18. Burger HG, Jameson JL, Loriaux DL, Marshall JC, Odell Smith D, Rayter S, Niederlander C, Spicer J, Jones C and WD, Potts JT, Rubinstein AH (eds). WB Saunders: Ashworth A. (2001). Hum. Mol. Genet., 10, 2869–2877. Philadelphia, PA. Smith DP, Houghton C and Ponder BAJ. (1997). Oncogene, The Breast Cancer Linkage Consortium. (1999). J. Natl. 15, 1213–1217. Cancer Inst., 91, 1310–1316. Smith SA, Easton DF, Evans DG and Ponder BA. (1992). Nat. The CHEK2-Breast Cancer Consortium. (2002). Nat. Genet., Genet., 2, 128–131. 31, 55–59.

Oncogene Review of 10 highly penetrant cancer syndromes R Nagy et al 6469 Thompson D and Easton D. (2002). Cancer Epidemiol. Vasen HFA, Watson P, Mecklin J-P and Lynch HT. (1999). Biomarkers Prev., 11, 329–336. Gastroenterology, 116, 1453–1456. Thompson D, Easton DF and the Breast Cancer Linkage Vasen HFA, Wijnen J and Menko F. (1996). Gastroenterology, Consortium. (2001). Am. J. Hum. Genet., 68, 410–419. 110, 1020–1027. Thorlacius S, Olafsdottir G, Tryggvadottir L, Neuhausen S, Vega QC, Worby CA, Lechner MS, Dixon JE and Dressler Jonasson JG, Tavtigian SV, Tulinius H, Ogmundsdottir HM GR. (1996). Proc. Natl. Acad. Sci. USA, 93, 10657–10661. and Eyfjord JE. (1996). Nat. Genet., 13, 117–119. Veraldi S, Cavicchini S, Benelli C and Gasparini G. (1991). Thorlacius S, Struewing JP, Hartge P, Olafsdottir GH, J. Am. Acad. Dermatol., 25, 632–636. Sigvaidason H, Tryggvadottir L, Wacholder S, Tulinius H Vojta PJ and Barrett JC. (1995). Biochim. Biophys. Acta, 1242, and Eyfjo¨rd JE. (1998). Lancet, 352, 1337–1339. 29–41. Toccalino H, Guastavino E, De Pinni F, O’Donnell J and Wagner A, Barrow A, Wignen J, van der Klift H, Franken P, Williams M. (1973). Acta Paediatr., 62, 337–342. Verkuijlen P, Nakagawa H, Geugien M, Jaghmohan- Tomlinson MJ and Bullimore JA. (1987). Br. J. Radiol., 60, Changur S, Breukell C, Meijers-Heijboer H, Morreau H, 89–90. van Puijenbroek M, Burn J, Coronel S, Kinarksi Y, Tonin P, Weber B, Offit K, Couch F, Rebbeck TR, Neuhausen Okimoto R, Watson P, Lynch JT, Lynch HT, de la Chapelle S, Godwin AK, Daly M, Wagner-Costalos J, Berman D, A and Fodde R. (2003). Am. J. Hum. Genet., 72, Grana G, Fox E, Kane MF, Kolodner RD, Krainer M, 1088–1100. Haber DA, Struewing JP, Warner E, Rosen B, Lerman C, Wagner A, Hendriks Y, Meijers-Heijboer E, de Leeuw W, Peshkin B, Norton L, Serova O, Foulkes WD, Lynch HT, Morreau H, Hofstra R, Tops C, Bik E, Brocker-Vriends A, Lenoir GM, Narod SA and Garber JE. (1996). Nat. Med., 2, van Der Meer C, Lindhout D, Vasen H, Breuning M, 1179–1183. Cornelisse C, van Krimpen C, Niermeijer M, Zwinderman Tonin PM, Mes-Masson AM, Narod SA, Ghadirian P and A, Wijnen J and Fodde R. (2001). J. Med. Genet., 38, Provencher D. (1999). Clin. Genet., 55, 318–324. 318–322. Treanor JJS, Goodman L, de Sauvage F, Stone DM, Wagner A, van der Klift H, Franken P, Wijnen J, Breukel C, Poulsen KT, Beck CD, Gray C, Armanini MP, Pollock Bezrookove V, Smits R, Kinarsky Y, Barrows A, Franklin RA, Hefti F, Phillips HS, Goddard A, Moore MW, B, Lynch J, Lynch H and Fodde R. (2002). Genes Buj-Bello A, Davies AM, Asai N, Takahashi M, Chromosomes Cancer, 35, 49–57. Vandlen R, Henderson CE and Rosenthal A. (1996). Nature, Waite KA and Eng C. (2002). Am. J. Hum. Genet., 70, 382, 80–83. 829–844. Trump D, Farren B, Wooding C, Pang JT, Besser GM, Wallis Y, Morton D, McKeown C and Macdonald F. (1999). Buchanan KD, Edwards CR, Heath DA, Jackson CE, J. Med. Genet., 36, 14–20. Jansen S, Lips K, Monson JP, O’Halloran D, Sampson J, Walon C, Kartheuser A, Michils G, Smaers M, Lannoy N, Shalet SM, Wheeler MH, Zink A and Thakker RV. (1996). Ngounou P, Mertens G and Verellen-Dumoulin C. (1997). Q. J. Med., 89, 653–669. Hum. Genet., 100, 601–605. Trupp M, Arenas E, Fainzilber M, Nilsson A-S, Sleber B-A, Wang Q, Zhang H, Kajino K and Greene MI. (1998). Grigoriou M, Kilkenny C, Salazar-Grueso E, Pachnis V, Oncogene, 17, 1939–1948. Arumae U, Sariola H, Saarma M and Iba´ nez CF. (1996). Warthin A. (1931). Ann. Int. Med., 4, 681–696. Nature, 381, 785–789. Watson P, Lin K and Rodriguez-Bigas MA. (1998). Cancer, Tsuzuki T, Takahashi M, Asai N, Iwashita T, Matsuyama M 83, 259–266. and Asai J. (1995). Oncogene, 10, 191–198. Wautot V, Vercherat C, Lespinasse J, Chambe B, Lenoir GM, Uchino S, Noguchi S, Sato M, Yamashita H, Yamashita H, Zhang CX, Porchet N, Cordier M, Beroud C and Calender Watanabe S, Murakami T, Toda M, Ohshima A, Futata T, A. (2002). Hum. Mutat., 20, 35–47. Mizukoshi T, Koike E, Takatsu K, Terao K, Wakiya Weber H, Venzon D, Lin J, Fishbein V, Orbuch M, Strader D, S, Nagatomo M and Adachi M. (2000). Cancer Res., 60, Gibril F, Metz D, Fraker D, Norton J and Jensen RT. 5553–5557. (1995). Gastroenterology, 108, 1637–1649. Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle Weng LP, Brown JL, Baker KM, Ostrowski MC and Eng C. A, Ruschoff J, Fishel R, Lindor NM, Burgart LJ, Hamelin (2002). Hum. Mol. Genet., 11, 1687–1696. R, Hamilton SR, Hiatt RA, Jass J, Lindblom A, Lynch HT, Weng LP, Brown JL and Eng C. (2001a). Hum. Mol. Genet., Peltomaki P, Ramsey SD, Rodriguez-Bigas MA, Vasen HF, 10, 599–604. Hawk ET, Barrett JC, Freedman AN and Srivastava S. Weng LP, Brown JL and Eng C. (2001b). Hum. Mol. Genet., (2004). J. Natl. Cancer Inst., 96, 261–268. 10, 237–242. van der Luijt R, Vasen H, Tops C, Breukel C, Fodde R and Weng LP, Gimm O, Kum JB, Smith WM, Zhou XP, Wynford- Meera Khan P. (1995). Hum. Genet., 96, 705–710. Thomas D, Leone G and Eng C. (2001c). Hum. Mol. Genet., van Weering D, Medema J, van Puijenbroek A, Burgering B, 10, 251–258. Baas P and Bos J. (1995). Oncogene, 11, 2207–2214. Weng LP, Smith WM, Brown JL and Eng C. (2001d). Hum. van Weering DH and Bos JL. (1998). Recent Results Cancer Mol. Genet., 10, 605–616. Res., 154, 271–281. Weng L-P, Smith WM, Dahia PLM, Ziebold U, Gil E, Lees Varley JM. (2003). Hum. Mutat., 21, 313–320. JA and Eng C. (1999). Cancer Res., 59, 5808–5814. Varley JM, McGown G, Thorncroft M, Santibanez-Koref Wiench M, Wygoda Z, Gubala E, Wloch J, Lisowska MF, Kelsey AM, Tricker KJ, Evans DG and Birch JM. K, Krassowski J, Scieglinska D, Fiszer-Kierzkowska A, (1997). Cancer Res., 57, 3245–3252. Lange D, Kula D, Zeman M, Roskosz J, Kukulska Vasen H, Stormorken A, Menko F, Nagengast F, Kleibeuker A, Krawczyk Z and Jarzab B. (2001). J. Clin. Oncol., 19, J, Griffioen G, Taal B, Moller P and Wijnen J. (2001). 1374–1380. J. Clin. Oncol., 19, 4074–4080. Wijnen J, de Leeuw W, Vasen H, van der Klift H, Mller P, Vasen HFA, Mecklin J-P, Meera Khan P and Lynch HT. Stormorken A, Meijers-Heijboer H, Lindhout D, Menko F, (1991). Dis. Colon Rectum., 34, 424–425. Vossen S, Mo¨slein G, Tops C, Bro¨cker-Vriends A, Wu

Oncogene Review of 10 highly penetrant cancer syndromes R Nagy et al 6470 YRH, Sijmons R, Cornelisse C, Morreau H and Fodde R. Zhang H, Somasundaram K, Peng Y, Tian H, Zhang H, Bi D, (1999). Nat. Genet., 23, 142–144. Weber B and El-Deiry WS. (1998). Oncogene, 16, 1713–1721. Wijnen JT, van der Klift H, Vasen H, Khan PM, Menko F, Zhou X, Woodford-Richens K, Lehtonen R, Kurose K, Tops C, Meijers HH, Lindhout D, Moller P and Fodde R. Aldred M, Hampel H, Launonen V, Virta S, Pilarski R, (1998). Nat. Genet., 20, 326–328. Salovaara R, Bodmer W, Conrad B, Dunlop M, Hodgson S, Wohlik N, Cote GJ, Bugalho MMJ, Ordonez N, Evans DB, Iwama T, Jarvinen H, Kellokumpu I, Kim J, Leggett B, Goepfert H, Khorana S, Schultz P, Richards CS and Gagel Markie D, Mecklin J, Neale K, Phillips R, Piris J, Rozen P, RF. (1996). J. Clin. Endocrinol. Metab., 81, 3740–3745. Houlston R, Aaltonen L, Tomlinson I and Eng C. (2001a). Woodford-Richens K, Williamson J, Bevan S, Young J, Am. J. Hum. Genet., 69, 704–711. Leggett B, Frayling I, Thway Y, Hodgson S, Kim J, Zhou XP, Hampel H, Thiele H, Gorlin RJ, Hennekam R, Iwama T, Novelli M, Sheer D, Poulsom R, Wright N, Parisi M, Winter RM and Eng C. (2001b). Lancet, 358, Houlston R and Tomlinson I. (2000). Cancer Res., 60, 210–211. 2477–2482. Zhou XP, Kuismanen S, Nystro¨m-Lahti M, Peltomaki P and Woods A, Johnstone SR, Dickerson K, Leiper FC, Fryer LG, Eng C. (2002a). Hum. Mol. Genet., 11, 445–450. Neumann D, Schlattner U, Wallimann T, Carlson M and Zhou XP, Loukola A, Salovaara R, Nystrom-Lahti M, Carling D. (2003). Curr. Biol., 13, 2004–2008. Peltoma¨ki P, de la Chapelle A, Aaltonen LA and Eng C. Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, (2002b). Am. J. Pathol., 161, 439–447. Collins N, Gregory S, Gumbs C and Micklem G. (1995). Zhou XP, Waite KA, Pilarski R, Hampel H, Fernandez Nature, 378, 789–792. MJ, Bos C, Dasouki M, Feldman GL, Greenberg LA, Wynford-Thomas D. (1999). J. Pathol., 187, 100–111. Ivanovich J, Matloff E, Patterson A, Pierpont ME, Russo Young R, Welch W, Dickersin G and Scully R. (1982). Cancer, D, Nassif NT and Eng C. (2003). Am. J. Hum. Genet., 73, 50, 1384–1402. 404–411.

Oncogene