Hereditary Colorectal Cancer. What You Need to Know

MedicineToday 2015; 16(2): 20-29

PEER REVIEWED FEATURE 2 CPD POINTS

Hereditary colorectal cancer Key points • Hereditary colorectal What you need to know cancer (CRC) syndromes are uncommon but their KATHY WU MB BS, MMed, FRACP; JUDY KIRK MB BS, FRACP diagnoses allow risk management to prevent Recognising hereditary colorectal cancer syndromes is important CRC and other malignancies. as there are implications for both patients and their families. General • Family history and personal practitioners are often the first point of patient contact, thereby playing history are essential for clinical diagnosis. a pivotal role in providing information and guidance. A balance between • Medicare and private health risk awareness and understanding of the benefits versus limitations of insurance do not fund genetic genetic testing is important. testing for most hereditary cancer syndromes. • Diagnostic genetic testing olorectal cancer (CRC) is the second most factors.2 Known hereditary CRC syndromes, has limitations, and is usually common malignancy in both men and caused by heritable highly penetrant single-gene reserved for patients meeting women in Australia, with an incidence of mutations, account for approximately 5% of clinical diagnostic criteria. approximately one in 10 for men and one all CRC cases.3 These syndromes, each of • Identification of a deleterious C 1 in 15 for women. It represents the second most which has its characteristic features, include gene mutation in a family common cause of cancer deaths after lung Lynch syndrome (2 to 4%), familial adenoma- allows ‘predictive testing’ cancer.1 tous polyposis (1%), MUTYH-associated (which can determine family CRC can be sporadic, familial or hereditary, polyposis (less than 1%) and hamartomatous members with/without the with sporadic CRC constituting the majority polyposis syndromes (less than 0.1%) such mutation) and also opens up of cases (65 to 85%). Approximately 20 to 30% as juvenile polyposis syndrome and Peutz-Jeghers reproductive options (e.g. of CRC is familial, with aetiology largely syndrome. pre-implantation genetic unknown and thought to be multifactorial, This article will focus on the currently known diagnosis). involving complex interactions between hereditary CRC syndromes. A glossary of some • eviQ Cancer Treatments genetic susceptibility and environmental terms used is provided in Box 1. Online (http://www.eviq.org. au) has guidelines on Dr Wu is Staff Specialist Clinical Geneticist at the Westmead Hospital Familial Cancer Service, Crown Princess referral, genetic testing and Mary Cancer Centre, and Clinical Senior Lecturer in Genetic Medicine at Westmead Clinical School, University of risk management, and Sydney, Sydney. Associate Professor Kirk is Director of the Westmead Hospital Familial Cancer Service, Crown information on familialCopyright _LayoutPrincess 1 17/01/12 Mary Cancer 1:43 PM Centre, Page and 4 Clinical Associate Professor of Medicine at Westmead Clinical School,

cancer clinics in Australia. Westmead Millennium Institute for Medical Research, University of Sydney, Sydney, NSW. © STEVE OH

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• Allele. One version of a gene at a given location (locus) along a chromosome. • Biallelic mutations. Mutations, either compound heterozygous (nonidentical) or homozygous (identical), that are present in both copies of a gene; usually THE ADENOMA–CARCINOMA SEQUENCE required for expression of an autosomal recessive disorder. CRC is usually preceded by adenomatous polyps, • De novo mutation. An alteration in a gene that occurs for the first time in a which originate from the glandular tissue of the family member, as a result of a spontaneous mutation occurring around the bowel and may become malignant if not removed. time of conception of this individual. In sporadic CRC, the transformation from ade- • Exome. The part of the genome formed by exons. Exons are joined together noma to carcinoma usually takes a number of after RNA splicing and removal of introns to form mature mRNA prior to years; in contrast, the adenoma–carcinoma protein translation. sequence associated with some hereditary CRC • Familial. A phenotype that occurs in more than one family member; may have syndromes, such as Lynch syndrome, evolves genetic or nongenetic aetiology. Nongenetic aetiology includes shared more rapidly.4 Surveillance colonoscopy with environmental or lifestyle factors. removal of polyps has been shown to be effective • Germline mutation. A gene mutation that can be passed to subsequent in preventing CRC and reducing CRC generations through germ (ova/sperm) cells. When inherited, such mutation is mortality.5 present in virtually every cell, including germ cells. In contrast, somatic Hamartomatous polyps are composed of the mutations arise later in life in the tissue cells of an individual and cannot be normal cellular elements of the gastrointestinal passed on to offspring. tract but have a disorganised architecture. They • Microsatellite instability (MSI). MSI is characterised by abnormal expansion grow along with, and at the same rate as, the or contraction of simple repetitive DNA sequences (i.e. microsatellite repeats) host tissue. The cancer pathogenesis associated that are ubiquitously present throughout the genome. MSI in coloretal cancer with hamartomatous polyposis syndromes is indicates a defect in one of the mismatch repair genes caused by either not fully defined. It has been postulated to somatic changes or a germline defect. involve malignant transformation occurring • Penetrance. The proportion of individuals with a gene mutation known to within co-existing adenomatous polyps, hamar- cause a disease who develop the associated phenotype. ‘Complete’ tomatous polyps undergoing adenomatous penetrance means that almost all individuals with a disease-causing mutation followed by carcinomatous transformation or, will invariably develop symptoms and signs of the disease; ‘incomplete’ or possibly, direct transformation from hamarto- ‘reduced’ penetrance means that not everyone with a disease-causing mas to carcinomas.6 mutation will develop the associated phenotype. • Pre-implantation genetic diagnosis (PGD). An intervention to achieve a TUMOUR PREDISPOSITION: THE pregnancy unaffected by a genetic disorder, via in vitro fertilisation (IVF), and KNUDSON ‘TWO-HIT’ HYPOTHESIS with the added step of screening the embryos for the family mutation so that Alfred Knudson’s ‘two-hit’ hypothesis describes only unaffected embryos are transferred back into the mother’s uterus for the the tumour predisposition associated with most pregnancy to continue. This intervention requires prior identification of the hereditary cancer syndromes. The hypothesis family mutation accounting for the genetic disorder. proposes that hereditary cancer is conferred by • Sporadic. Occurrence of a disorder caused by nongenetic factors. a germline mutation (representing the first hit) affecting one allele of a gene in every cell, with tumour developing only after the other allele of • genes involved in critical cellular pathways the gene is mutated (the second hit), the latter such as the transforming growth factor-beta being a somatic change triggered by environ- (TGF-beta) pathway (e.g. BMPR1A/ mental and/or other genetic factors. SMAD4 genes associated with juvenile The genes in which germline mutations lead polyposis syndrome). to tumour formation can be broadly categorised into: HOW ARE HEREDITARY CRC SYNDROMES • tumour suppressor genes with loss of DIAGNOSED? function mutations (e.g. APC gene Each of the hereditary CRC syndromes has its associated with familial adenomatous own distinctive constellation of clinical features polyposis; STK11 gene associated with allowing its recognition and diagnosis, as Peutz-Jeghers syndrome) summarised in the Table and flowchart. • genes involved in DNA repair (e.g. Establishing a clinical diagnosis, by ascer- mismatch repair genes associated with taining a family history of related tumours (e.g. Lynch syndromeCopyright and MUTYH _Layout-associated 1 17/01/12 1:43multiple PM Page affected 4 close relatives on the same polyposis) side of family with same/related malignancies

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TABLE. SUMMARY OF MAJOR COLORECTAL CANCER PREDISPOSITION SYNDROMES

Syndrome % CRC Associated Key features Risk management7 cases gene(s)

N onpolyposis

Lynch 2–4% Mismatch • No/few polyps • Annual colonoscopy from age 25 years syndrome repair (MMR) • MMR deficient and/or microsatellite • Consider biennial gastroscopy from (LS) genes: MLH1, unstable tumours age 30 years in families with gastric MSH2, MSH6, • Risk of other malignancies: cancer or those at high ethnic risk PMS2 endometrial (up to 60% lifetime risk); • Risk-reducing hysterectomy and less frequently ovarian, gastric, small bilateral salpingo-oophorectomy by bowel, hepatobiliary, urothelial, brain age 40 years and sebaceous tumours

Adenomatous polyposis

Familial 1% APC • Hundreds to thousands of • Annual or biennial sigmoidoscopy/ adenomatous adenomatous polyps colonoscopy from age 12 to 15 years, polyposis • Young onset polyps/CRC then annual colonoscopy at onset of (FAP) • Variable features: polyps of gastric polyps fundus, duodenum or small bowel, • Prophylactic colectomy when polyp duodenal carcinoma, desmoid tumours, burden high, usually by late teens osteomas, congenital hypertrophy of • Upper GI endoscopy from age 25 years retinal pigment epithelium

MUTYH- <1% MUTYH • Autosomal recessive inheritance • Colonoscopy from age 20 years, associated • Attenuated polyposis phenotype biennially if no polyps detected, polyposis (polyp count range, 1 to 100) annually when polyps detected until (MAP) • Variable features: duodenal/gastric colectomy is indicated fundic polyps, extraintestinal tumours • Upper GI endoscopy from age 25 years

Serrated polyposis

Serrated Unknown Unknown • Polyps are frequently small and flat, • Patients with SPS: colonoscopy every polyposis making endoscopic detection difficult 1 to 3 years depending on polyp syndrome • Co-occurrence of adenomatous number and size (SPS) polyps is common • Unaffected FDR (without polyps) of • Aetiology unknown, inherited patients with SPS: consider colonoscopy component implicated although every 3 to 5 years from age 40 years or inheritance pattern not clear 10 years younger than youngest age at • Genetic testing not available diagnosis of SPS-related CRC at younger ages) as well as a personal HOW DOES GENETIC TESTING WORK? member (the index case) and searching for history (e.g. polyp count/histology and Mutation search mutations in targeted genes. This may take presence of extracolonic manifestations), If a clinical diagnosis of hereditary CRC is some months. is essential prior to considering genetic suspected, the index case should be referred At present, molecular genetic testing in testing (Box 2; Figures 1a to c and Figures to a familial cancer clinic for assessment, its traditional sense is limited by its ability 2a to d). A family history may not always genetic counselling prior to testing if to find causative gene mutations because be present, as the patient may be the first indicated, and risk management, bearing in many cases more than one gene may be to be affected in the family (caused by a in mind that diagnostic genetic testing is implicated and/or the disease may be de novo mutation). The lack of family only warranted in a minority of patients. caused by mutations in an unknown gene/ history may also be due to small family This initial step in molecular diagnosis, genes. Testing is, therefore, only beneficial size, premature deathCopyright or _Layoutincomplete 1 17/01/12 called 1:43 ‘mutation PM Page search’, 4 involves taking a for those families meeting stringent clinical penetrance. blood sample from an affected family diagnostic criteria.

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Syndrome % CRC Associated Key features Risk management7 cases gene(s)

Hamartomatous polyposis

Juvenile <0.1% BMPR1A, • ‘Juvenile’ refers to a particular type • Before polyps develop: biennial polyposis SMAD4 of hamartomatous polyp colonoscopy (from age 15 years) syndrome (each • Mostly benign, malignant and upper GI endoscopy (from age (JPS) accounting for transformation may occur 25 years) 20% of JPS • May cause bleeding, protein-losing • Annual surveillance if polyps present cases) enteropathy • Consider prophylactic colectomy if • Cases due to SMAD4 mutation high polyp burden may present with combined JPS • Hereditary haemorrhagic telangiectasia and hereditary haemorrhagic evaluation in those with SMAD4 telangiectasia mutation

Peutz- <0.1% STK11 • PJS-type hamartomatous polyps in • GI surveillance from age 10 years, Jeghers small bowel and/or elsewhere for detection and removal of polyps syndrome • Characteristic mucocutaneous to prevent complications: annual (PJS) pigmentation haemoglobin; video capsule • Major morbidity in children relates to endoscopy or magnetic resonance intestinal intussusception endoscopy at least every 3 years; • Risk of adult-onset cancers: breast, upper GI endoscopy and colonoscopy gynaecological, pancreatic at least every 3 years • Above GI screening to continue through adulthood for cancer surveillance • Breast cancer screening from age 30 years • Pap smear and pelvic examination from age 18 years

ABBREVIATIONS: CRC = colorectal cancer; FDR = first-degree relative; GI = gastrointestinal; MMR = mismatch repair.

Predictive genetic testing Funding and the future Unlike traditional Sanger sequencing Once a causative gene mutation is identi- In Australia, Medicare and private health (testing single genes at a time), NGS has fied in an index case, his or her close rel- insurance do not fund genetic testing for the capacity of simultaneously analysing atives can then be offered ‘predictive’ most hereditary cancer syndromes. If tens of thousands of genes. NGS technology genetic testing to determine whether or testing is deemed warranted as assessed has led to the discovery of new CRC- not they have the family gene mutation. by a familial cancer clinic, publicly funded predisposition genes through whole- This takes several weeks. Predictive genetic testing is available through the clinic genome or whole-exome sequencing (e.g. testing can definitively determine which budgeted by the state and territory health POLE and POLD1 genes, which encode family members are at higher cancer risk departments. Self-funded testing is possi- DNA polymerase enzymes important in and thus would benefit from risk manage- ble and can be facilitated by the clinic, with DNA replication and repair, with mutation ment. It can also determine those who do important pre- and post-test counselling phenotype yet to be fully characterised).8 not have the family gene mutation, in provided. The cost of testing varies NGS has also enabled the use of multiplex which case they are at average cancer risk depending on the gene involved and the panels for simultaneous sequencing of and can be spared unnecessary screening technology used, but ranges from a few multiple known CRC susceptibility genes and concern. hundred to a few thousand dollars. in individual patients.9,10 Furthermore, once a causative gene As with the trend worldwide, familial Concerns regarding the use of NGS mutation is identified in the family, it opens cancer clinics across Australia are moving include bioinformatic challenges, data up reproductive optionsCopyright such _Layout as 1pre- 17/01/12 towards 1:43 thePM use Page of next-generation 4 sequenc- interpretation and the potential return of implantation genetic diagnosis (PGD). ing (NGS) technology as a diagnostic tool. incidental findings.11 Despite these, it is

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AN APPROACH TO DIAGNOSING HEREDITARY COLORECTAL CANCER SYNDROMES

Patient presents with colorectal cancer and/or polyps

No or few polyps Many polyps – polyposis syndrome

Adenomas Serrated polyps Hamartomatous polyps Colorectal cancer with MMR protein deficiency or microsatellite instability

100 or more 10 to 100 Characteristic Juvenile* adenomas adenomas mucocutaneous pigmentation Lynch syndrome Serrated Associated cancers: polyposis • endometrial Autosomal Autosomal syndrome • ovarian dominant recessive • urothelial inheritance inheritance Peutz-Jeghers Juvenile syndrome polyposis Associated cancers: syndrome Familial adenomatous MUTYH-associated • female breast polyposis/attenuated familial polyposis syndrome adenomatous polyposis • gynaecological Associated features: • pancreatic • desmoid tumours • duodenal adenoma/carcinoma

• gastric fundic adenoma ABBREVIATION: MMR = mismatch repair. • dental anomalies * Juvenile polyp refers to a particular histological subtype of hamartomatous polyps, rather than the age of onset. anticipated that NGS-based testing will be be performed annually, rather than dictated as hereditary nonpolyposis colon cancer, widely used in clinical practice in the near by the number of polyps found. Moreover, is the most common form of hereditary future, driven partly by the lower cost of many of these hereditary CRC syndromes CRC, accounting for 2 to 4% of incident NGS-based testing compared with the are associated with predisposition to extra- CRC, and has a population incidence of 1 traditional targeted strategy involving colonic tumours, and diagnosis allows effec- in 440.3,13 It is characterised by inherited Sanger sequencing. tive risk-reducing strategies to be undertaken predisposition to CRC, often with younger appropriately, thus reducing overall cancer ages of onset (up to 80% lifetime risk, mean WHY DIAGNOSE HEREDITARY CRC incidence. age at diagnosis ranging from 44 to 61 SYNDROMES? The website eviQ Cancer Treatments years), as well as endometrial cancer (up to Recognising hereditary CRC syndromes is Online, developed by Cancer Institute NSW, 60% lifetime risk) and, less frequently, can- important because these syndromes con- is an online resource for national guidelines cers of the ovary, stomach, small bowel, stitute a group where molecular diagnosis, on referral, genetic testing and risk manage- hepatobiliary tract and urinary tract as well identification of unaffected at-risk family ment for various cancer genetic syndromes, as brain (Turcot variant) and sebaceous members via predictive genetic testing, and including hereditary CRC syndromes tumours (Muir-Torre variant).14 implementation of early screening at more (http://www.eviq.org.au).12 It is widely used LS is an autosomal dominant condition frequent intervals would prevent CRC and by familial cancer clinics across Australia, caused by a germline mutation in one of the reduce CRC mortality. In addition, the man- as well as by other health professionals. mismatch repair (MMR) genes, namely agement of the index patient may be different MLH1, MSH2, MSH6 or PMS2. The MMR if the underlying diagnosis is known. For HEREDITARY CRC SYNDROMES genes encode the MMR proteins, which play example, a diagnosisCopyright of Lynch _Layout syndrome 1 17/01/12 Lynch 1:43 syndromePM Page 4 an important role in error-proofing during means that surveillance colonoscopy should Lynch syndrome (LS), previously known DNA replication.15 LS-associated tumours

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2. PERSONAL AND FAMILY HISTORY CHARACTERISTICS SUGGESTIVE OF A HEREDITARY COLORECTAL CANCER SYNDROME

Personal history • Age of onset (typically <50 years) • High number of polyps • More than one primary cancer (synchronous or metachronous CRC; other associated cancers) • Presence of rare tumours (e.g. Figures 1a to c. Endoscopic appearances of different gastrointestinal polyps. a (left). sebaceous tumours) Conventional adenoma, attached to the bowel mucosa via a stalk. b (centre). Numerous • Presence of extracolonic features polyps seen in a patient with familial adenomatous polyposis. c (right). Sessile polyp, (e.g. desmoid tumours) showing the flattened and broad-based appearance, making its detection difficult. • Tumour testing (e.g. MMR protein- deficient CRC) FIGURES 1A AND 1C REPRODUCED COURTESY OF PROFESSOR MICHAEL BOURKE, SYDNEY, NSW.

Family history 7 • Number of affected relatives testing) has been shown to be potentially Japanese). Currently there is insufficient 21 (typically three or more) on the same effective. Some centres in Australia have evidence to routinely recommend risk- side of family adopted universal screening. reducing medication, such as aspirin. • Closeness of affected relatives It should be noted that approximately Risk-reducing hysterectomy and bilat- (first- or second-degree) 12% of sporadic CRCs display MSI and/or eral salpingo-oophorectomy are recom- • Presence of related tumours (e.g. are MLH1-deficient on immunohistochem- mended when childbearing is complete or 22 CRC and endometrial cancers) istry. This occurs as a result of somatic by age 40 years, as there is no effective • Young age of onset of tumours MLH1 hypermethylation, rather than an screening for endometrial or ovarian MLH1 germline mutation.23 In CRCs dis- cancers. It is recommended that patients ABBREVIATIONS: CRC = colorectal cancer; MMR = mismatch repair. playing MSI or MLH1 deficiency, especially be referred to experienced hands such as a in those patients diagnosed at relatively gynaecological oncologist for such risk- older ages, BRAF tumour testing may help reducing surgeries. are deficient in the MMR protein (MMR- distinguish between sporadic cases (BRAF deficient), thereby displaying immunohisto mutation present) and those associated with Familial adenomatous polyposis chemical loss of relevant MMR proteins and LS (BRAF-wild type), as somatic BRAF Familial adenomatous polyposis (FAP) is a microsatellite instability (MSI).16 The lifetime mutations are associated with sporadic colon cancer predisposition syndrome char- cancer risks associated with LS vary accord- CRCs that develop through the methylation acterised by the development of h undreds ing to the specific MMR gene involved.17 pathway.24,25 to thousands of precancerous colonic ade- Historically, the diagnosis of LS was nomatous polyps, with a mean age of polyp suspected based on clinical criteria, namely Risk management onset of 16 years (range 7 to 36 years) and a the Amsterdam I/II criteria and/or the Identifying individuals with LS is important more than 95% lifetime CRC risk in (revised) Bethesda guidelines (Box 3).18,19 because colonoscopic surveillance reduces untreated individuals (Figures 1b and 2a).29 However, tumour testing is now widely CRC mortality and prophylactic surgery It accounts for 1% of CRC.30 Variable extra- utilised (immunohistochemistry and/or substantially reduces the risk of gynaecolog- colonic manifestations include those that are MSI testing) and this has high sensitivity ical cancers in both index cases and at-risk potentially life-threatening, such as duodenal and specificity for LS.20 Furthermore, the relatives.26-28 According to eviQ risk man- adenomas/carcinomas and desmoid lack of a specific MMR protein via immu- agement guidelines, annual colonoscopy is tumours, as well as those that are clinically nohistochemistry can also direct germline recommended in individuals with LS from benign, such as gastric fundic polyps, osteo- testing of that specific gene. More recently, the age of 25 years, and second-yearly mas, congenital hypertrophy of the retinal population-based screening for LS (uni- gastroscopy should be considered from the pigment epithelium and dental anomalies. versal screening of all incident CRC for age of 30 years for those with a family history Attenuated FAP (aFAP) is characterised MMR deficiency andCopyright subsequent _Layout referral 1 17/01/12 of gastric 1:43 PM cancer Page or 4 who are at high ethnic by the presence of fewer colonic polyps for consideration of germline genetic risk (e.g. Chinese, Korean, Chilean and (average 30, and more proximally located) © FIGURE 1B: DAVID M. MARTIN/SPL

26 MedicineToday x FEBRUARY 2015, VOLUME 16, NUMBER 2 Downloaded for personal use only. No other uses permitted without permission. © MedicineToday 2015. and/or polyps occurring at an older age compared with classic FAP, and usually there are no extracolonic manifestations. FAP and aFAP are autosomal dominant conditions caused by a germline mutation in the APC gene. This tumour suppressor gene encodes adenomatous polyposis coli (APC) protein, which plays a critical role in many cellular processes. Gardner and Tur- cot syndromes historically refer to the asso- ciation of colonic polyposis typical of FAP and osteomas/soft tissue tumours or central nervous system tumours, respectively, prior to the identification of the APC gene. Testing for FAP should be considered for individuals with multiple colonic polyps, especially in, but not limited to, those with a family history consistent with an auto somal dominant inheritance. In the past, before the availability of genetic testing, all at-risk relatives (e.g. siblings and children of Figures 2a to d. Histological features (haematoxylin-eosin stain) of different gastro- those with clinical FAP) had to be screened intestinal polyps. a (top left). Colonic microtubular adenoma from a patient with familial annually for polyps from age 12 years. Now, adenomatous polyposis, showing mild cytological dysplasia involving superficial for most families, a causative gene mutation portion of only a few adjacent crypts. b (top right). Colonic sessile serrated adenoma can be found with ‘mutation search’ in the showing extension of the serrations to the crypt base with dilated inverted T- or index case, then ‘at-risk’ relatives can be L-shaped crypts, reflecting disordered proliferation. c (bottom left). Juvenile polyp of tested in the early teenage years to determine colon typically displaying mucus-filled dilated crypts, expanded lamina propria with their need for bowel screening. inflammatory infiltrate and, unlike Peutz-Jeghers-type hamartomatous polyps, absence of smooth muscle proliferation. d (bottom right). Intestinal Peutz-Jeghers syndrome Risk management polyp showing characteristic arborising pattern of smooth muscle proliferation. For patients with FAP and their relatives FIGURES 2A TO D REPRODUCED COURTESY OF DR DUNCAN MCLEOD, SYDNEY, NSW. identified to have the family APC gene mutation, screening (with annual or by biallelic mutations in the MUTYH gene. Risk management biennial sigmoidoscopy/colonoscopy from This gene encodes the protein mutY homo- Clinical care of patients and their relatives age 12 to 15 years, and then annual colo- logue (MYH) glycosylase, which is involved with MAP is similar to that of those with noscopy once polyps start developing) and in DNA base excision repair. familial adenomatous polyposis. Colonos- ultimately prophylactic colectomy (which Patients with MAP exhibit an attenuated copy is recommended from age 20 years, is standard of care once polyp burden is polyposis phenotype (mean polyp count, on a biennial basis if no polyps are detected, high, usually by the late teens) results in a 50; range, one to 100), with a lifetime CRC and annually when polyps are detected, significant reduction in CRC diagnosis.7,31 risk of 85% without treatment.32,33 MAP until colectomy is indicated. Upper gastro- Annual surveillance of residual rectum accounts for approximately less than 1% of intestinal endoscopy is recommended from or ileal pouch is required following colec- all CRC cases.32,34 Other features variably the age of 25 years.7 tomy. Upper gastrointestinal endoscopy is associated with MAP include duodenal/ recommended from the age of 25 years, with gastric fundic polyps and extraintestinal Serrated polyposis syndrome frequency dependent on the findings.7 There neoplasias.35 Previously known as hyperplastic polyposis is no evidence to routinely recommend sur- For patients with 10 or more colorectal (HP), serrated polyposis syndrome (SPS) is veillance for extraintestinal tumours. adenomas, especially if no germline APC a syndrome of unknown genetic basis char- mutation has been identified and the family acterised by the development of multiple MUTYH-associated polyposis history is compatible with recessive inher- ‘serrated’ polyps in the colorectum and MUTYH-associatedCopyright polyposis _Layout (MAP) 1 17/01/12 is itance, 1:43 genetic PM Page testing 4 of MUTYH may be associated with an increased CRC risk.36 an autosomal recessive condition caused indicated. These polyps have characteristic macro- and

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3. CLINICAL CRITERIA FOR IDENTIFICATION OF PATIENTS microscopic appearances (flattened and syndrome-type hamartomatous polyps, WITH SUSPECTED LYNCH SYNDROME broad-based endoscopically, referred to as absence of smooth muscle proliferation sessile; and a saw tooth appearance under (Figure 2c).42 Most juvenile polyps are Amsterdam II criteria18 the microscope, referred to as serrated) benign, but they may cause bleeding, The fulfilment of all the criteria listed (Figures 1c and 2b). Co-occurrence of con- anaemia and/or protein-losing enteropathy. below identifies patients with LS, with a ventional adenomas in the large intestine Malignant transformation can occur, with 36 sensitivity of 22% (range 13 to 67%) is common. an associated lifetime CRC risk of 30 to and a specificity of 98% (range 97 to Up to 40% of patients with SPS have a 40%, and to a lesser degree upper gastro 43-45 100%)17 family history of CRC, and occasionally SPS intestinal cancers. • Three or more relatives with may occur in more than one family member, It should be noted that solitary colorectal 37 confirmed LS-associated cancer*, implicating an inherited component. How- juvenile polyps occur in approximately 2% one of whom is a first-degree relative ever, no associated genes have been identi- of children. These polyps are sporadic and of the other two fied, so no genetic testing is available. are not known to be associated with an 46 • Two or more successive generations A clinical diagnosis of SPS is made based increased risk of gastrointestinal cancer. 38 affected with LS-associated cancer on the WHO diagnostic criteria: Two genes known to be associated with • One or more LS-associated cancer • at least five serrated polyps proximal to JPS are BMPR1A and SMAD4, each diagnosed before age 50 years the sigmoid colon, with two or more accounting for approximately 20% of JPS 47 • Familial adenomatous polyposis is polyps being more than 10 mm, or cases. These genes encode bone morpho- excluded • more than 20 serrated polyps of any genetic protein receptor type 1A and SMAD size distributed throughout the family member 4 protein, respectively, both Revised Bethesda guidelines19 colon, or of which are involved in the transforming These guidelines identify CRC cases • any number of serrated polyps growth factor-beta (TGF-beta) signalling where tumour testing is indicated. The proximal to the sigmoid colon in an pathway that, in turn, modulates many fulfilment of any of the criteria listed individual who has a first-degree important cellular processes, including pro- below has a sensitivity of 82% (range relative with SPS. liferation and differentiation.48 The genetic 78 to 91%) and a specificity of 77% aetiology of the remaining 60% of clinical (range 75 to 79%) for LS17 Risk management JPS cases is unknown. Approximately 20% • CRC diagnosed before age 50 years In patients with SPS, colonoscopy is of individuals with a SMAD4 mutation may • Presence of synchronous or recommended every one to three years present with a combined syndrome of JPS metachronous LS-associated depending on the number and size of and hereditary haemorrhagic telangiecta- cancers* polyps.7 In unaffected individuals (without sia,49the latter being a generalised vascular • CRC diagnosed before age 60 years polyps) who have a first-degree relative with malformation disorder. with pathology features suggestive SPS, the risk of CRC is unclear but it is rea- Genetic testing for the two known genes of high-level microsatellite instability† sonable to consider colonoscopy every is available if the patient fulfils the following • Patient with CRC and at least one three to five years from the age of 40 years clinical diagnostic criteria:42 first-degree relative with a or from 10 years younger than the age at • more than five juvenile polyps of the LS-associated cancer diagnosed diagnosis of the youngest person with CRC colorectum, or before age 50 years related to SPS in the family.39,40 • multiple juvenile polyps throughout • Patient with CRC and at least two the gastrointestinal tract, or first- or second-degree relatives Juvenile polyposis syndrome • any number of juvenile polyps and a diagnosed with a LS-associated Juvenile polyposis syndrome (JPS) is an family history of JPS. cancer at any age autosomal dominant predisposition to ABBREVIATIONS: CRC = colorectal cancer; multiple hamartomatous gastrointestinal Risk management LS = Lynch syndrome. polyps with age of onset often before Colonoscopy and upper endoscopy are * LS-associated cancers include colorectal, 41 endometrial, ovarian, gastric, small bowel, urothelial, 20 years. The term ‘juvenile’ refers to the recommended for patients with JPS and hepatobiliary tract and brain cancers, and sebaceous type of polyps, which are hamartomas with at-risk relatives, on a biennial basis from gland carcinomas/adenomas. a distinct histology differing from that of the ages of 15 years and 25 years, respec- † Pathology features suggestive of high-level adenomas, rather than to the age of onset. tively, before polyps develop; and annually microsatellite instability include Crohn’s-like 7 lymphocytic infiltration, mucinous/signet cell Histologically, juvenile polyps display if polyps are present. Prophylactic colec- Copyright _Layout 1 17/01/12 1:43 PM Page 4 differentiation and/or medullary growth pattern. mucus-filled dilated glands, inflammatory tomy can be considered if polyp burden is infiltrate and, unlike Peutz-Jeghers high. Additionally, all patients with JPS

28 MedicineToday x FEBRUARY 2015, VOLUME 16, NUMBER 2 Downloaded for personal use only. No other uses permitted without permission. © MedicineToday 2015. typically displaying an arborising strategies are available to prevent associated pattern of smooth muscle proliferation cancers in both index patients and at-risk (Figure 2d), or54 family members. Personal and family his- • any number of PJS-type polyps in an tories are essential in establishing a clinical individual who also has characteristic diagnosis, and should be ascertained prior mucocutaneous pigmentation to considering genetic testing. Familial (Figure 3), or cancer clinics provide patients with infor- • any number of PJS-type polyps in mation, support and guidance on deci- one individual who has a family sion-making for genetic testing, cancer risk history of PJS in a close relative(s), or management, and family/life planning. Figure 3. Characteristic mucocutaneous • characteristic mucocutaneous Despite the promise offered by next gen- pigmentation associated with Peutz- pigmentation in an individual who eration sequencing as a diagnostic tool, Jeghers syndrome. This can occur has a family history of PJS in a close determining family history and establishing around the mouth, eyes and nostrils, relative(s). an accurate clinical diagnosis remain crucial. on the fingers and buccal mucosa and The majority of patients with clinical PJS As we enter the genomic era, it is anticipated in the perianal area, and is most have a germline mutation in the STK11 gene, that familial cancer clinics will play an even pronounced in early childhood and which is a tumour suppressor gene encoding greater and more challenging role in inter- may fade in puberty/adulthood. the serine/threonine kinase 11 protein. preting complex genomic information that will be used to achieve both personalised Risk management cancer care and cancer prevention. MT caused by a SMAD4 mutation should be Gastrointestinal surveillance is recom- evaluated for the symptoms and signs of mended to start from age 10 years, with REFERENCES hereditary haemorrhagic telangiectasia, annual haemoglobin levels together with including pulmonary and cerebral arterio video capsule endoscopy or magnetic A list of references is included in the website version venous malformations. resonance endoscopy, as well as upper (www.medicinetoday.com.au) and the iPad app endoscopy and colonoscopy, at least every version of this article. Peutz-Jeghers syndrome three years.7 Screening at such a young age Peutz-Jeghers syndrome (PJS) is an autoso- is aimed at reducing morbidities associated COMPETING INTERESTS: None. mal dominant condition characterised by with intussusception, which is a major com- gastrointestinal hamartomatous polyposis, plication that invariably leads to surgical Online CPD Journal Program mucocutaneous pigmentation and cancer resection of large segments of intestine, and predisposition (Figure 3). The PJS-type can be prevented by timely detection and hamartomatous polyps are usually benign removal of polyps. At present, there is lim- and occur most commonly in the small ited literature documenting the effectiveness intestine, although they can occur anywhere of gastrointestinal cancer surveillance in within, and rarely outside, the g astrointestinal PJS.52,55 Nevertheless, expert opinion tract.50,51 The age of polyp onset is variable, recommends that the above screening mostly in the mid-teenage years but can be regime be continued through adulthood.7 as early as the first few years of life. The polyps Furthermore, breast cancer screening may cause complications such as bowel should start from age 30 years, with annual obstruction, intussusception, bleeding and/ clinical examination and mammogram, or anaemia.51 Affected individuals are at as well as MRI if available. Bilateral risk- © SEBASTIAN KAULITZKI/SHUTTERSTOCK increased risk for a wide variety of malig- reducing mastectomy can be considered Known hereditary colorectal nancies (which are usually of adult onset), following counselling at a familial cancer cancer (CRC) syndromes account including g astrointestinal (up to 57% lifetime clinic. Gynaecological surveillance is rec- for what proportion of all CRCs? risk), female breast, gynaecological and ommended from age 18 years with biennial Review your knowledge of this topic pancreatic cancers.52 Pap smear and pelvic examination.7 and earn CPD points by taking part in The diagnosis of PJS is based on clinical MedicineToday’s Online CPD Journal Program. findings:53 CONCLUSION Log in to Copyright _Layout 1 17/01/12 1:43 PM Page 4 • two or more histologically confirmed Recognising hereditary CRC syndromes is www.medicinetoday.com.au/cpd

MedicineToday x FEBRUARY 2015, VOLUME 16, NUMBER 2 29 Downloaded for personal use only. No other uses permitted without permission. © MedicineToday 2015. MedicineToday 2015; 16(2): 20-29 Hereditary colorectal cancer What you need to know

KATHY WU MB BS, MMed, FRACP; JUDY KIRK MB BS, FRAC

REFERENCES

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