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The Genetics of Hereditary Colon Cancer

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The Genetics of Hereditary Colon Cancer Downloaded from genesdev.cshlp.org on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW The genetics of hereditary colon cancer Anil K. Rustgi1 Dapartment of Medicine (Gastrointestinal), Department of Genetics, and Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA The genetic basis of sporadic colorectal cancer has illu- families with hereditary forms of colorectal cancer. In minated our knowledge of human cancer genetics. This parallel fashion, an appreciation of the biological under- has been facilitated and catalyzed by an appreciation and pinnings of colorectal cancer has been transformed deep understanding of the forms of colorectal cancer that through mouse models and delineation of molecular harbor an inherited predisposition, including familial ad- pathways that were predicated upon how these pathways enomatous polyposis (FAP), hereditary nonpolyposis operate to foster different forms of hereditary colorectal colorectal cancer (HNPCC) or Lynch syndrome, the cancer. hamartomatous polyposis syndromes, and certain other In assessing the annual cases of colorectal cancer in rare syndromes. Identification of germline mutations in the United States, it is clear that a distinction should be pivotal genes underlying the inherited forms of colorec- made for what is truly hereditary and what is in actuality tal cancer has yielded many dividends, including func- familial. The former connotes a distinct genetic basis tional dissection of critical molecular pathways that that has been defined, whereas the latter comprises an have been revealed to be important in development, cel- increased predisposition to cancer but without determi- lular homeostasis, and cancer; new approaches in che- nation, as of yet, as whether there is a hereditary basis moprevention, molecular diagnostics and genetic test- with discovery of pertinent tumor suppressor genes that ing, and therapy; and underscoring genotypic–pheno- are inactivated in the germline or whether the predispo- typic relationships. sition is stochastic. In that context, it is estimated that perhaps 20%–30% of all colorectal cancers have a famil- ial basis. A study of 34 kindreds revealed that there is Colorectal cancer is a common cancer in the United genetic susceptibility to sporadic colorectal adenoma- States and worldwide. There are nearly 150,000 new tous polyps and colorectal cancer (Cannon-Albright et al. cases annually in the United States (http://www.cancer. 1988, 1989). Ongoing efforts should be fruitful in deci- ∼ org/docroot/stt/stt_0.asp) and 900,000 cases worldwide phering the potential polygenic basis for familial colo- (http://www.who.int/en). Colorectal cancer-related mor- rectal cancer. These will be achieved through careful se- tality comprises nearly 55,000 cases annually in the lection of families for genome-wide studies. An example United States (http://www.cancer.org/docroot/stt/stt_0. is found in the study of nearly 60 kindreds in which asp). The lifetime risk of colorectal cancer in the average- siblings less than age 65 had colorectal cancer but with- risk person, defined as without personal history or fam- out evidence of hereditary colorectal cancer syndromes. ily history of colorectal cancer and above the age of 50, is This led to genetic linkage to human chromosome 5%–6%. This increases anywhere up to 20% when there 9q22.2-31.2 (Wiesner et al. 2003). is involvement of first-degree and/or second-degree rela- Hereditary colorectal cancer syndromes, especially tives with colorectal cancer, and reaches a lifetime risk with an emphasis on biology and genetics and their re- of 80%–100% in hereditary colorectal cancer syndromes, lationship to phenotypic manifestations, form the basis such as in hereditary nonpolyposis colorectal cancer for this review (Table 1). Approximately 3%–4% of colo- (HNPCC) and familial adenomatous polyposis (FAP), re- rectal cancer cases are attributable to HNPCC or Lynch spectively. syndrome, and the slight variation is due likely to geog- An explosion of information and insights into the mo- raphy and ethnicity. Nearly 1% of colorectal cancer lecular pathogenesis of sporadic colorectal cancer dates cases are due to FAP. Less than 1% of cases are due to a back to the late 1980s, and since has served as a paradigm panoply of conditions, namely, MYH-associated polypo- for the investigation of cancer genetics in general, and sis (MAP), the hamartomatous polyposis syndromes, and the emergence of novel diagnostics and therapeutics in hyperplastic polyposis. cancers as well. Much of this was fueled by the identifi- cation, characterization, and elucidation of probands and FAP [Keywords: Colon cancer; hereditary; polyposis; syndromes] FAP is an autosomal dominant mode disorder that af- 1Correspondence. E-MAIL [email protected]; FAX (215) 573-5412. fects one in 13,000 births (Bisgaard et al. 1994). The most Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1593107. compelling feature is the onset and progression of hun- GENES & DEVELOPMENT 21:2525–2538 © 2007 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/07; www.genesdev.org 2525 Downloaded from genesdev.cshlp.org on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press Rustgi Table 1. Hereditary gastrointestinal polyposis syndromes these were nonsense mutations, resulting in a truncated Familial adenomatous polyposis (FAP) (APC) protein with a broad range of molecular masses less than Attenuated FAP (APC) the predicted 310-kDa (2843 amino acids) wild-type APC Turcot syndrome (nearly two-thirds with germline APC protein. Some of these germline mutations correlated mutation; one-third with germline MMR mutation) with phenotypic manifestations, such as CHRPE, the se- MYH-associated polyposis (MYH) verity of polyposis, and an attenuated form of FAP, des- Hereditary nonpolyposis colorectal cancer (HNPCC) or ignated as attenuated APC (AAPC) or attenuated FAP Lynch syndrome (MSH2, MLH1, MSH6, PMS2) (Fig. 1). Alternative splicing of the APC gene 5Ј to exon 1 Muir-Torre syndrome generates isoforms that may regulate cell growth and Familial colorectal cancer X (genetic basis unknown) differentiation (Carson et al. 2004); additionally, other Hamartomatous polyposis syndromes Peutz-Jeghers (PJ) syndrome (LKB1) exon(s) can be alternatively spliced. Attenuated FAP is Ј Ј Familial Juvenile Polyposis (FJP) (SMAD4, BMPR1A, ENG) highlighted by mutations in either the extreme 5 or 3 Cowden’s syndrome (PTEN) ends of the APC exons (Spirio et al. 1993), and this may Bannayan-Ruvalcaba-Riley (BRR) syndrome (PTEN) influence potentially the stability of the APC protein Gorlin’s syndrome (PTCH) with markedly delayed onset of and a diminished range Hereditary mixed polyposis syndrome (genetic basis of clinical manifestations (e.g., fewer colonic adenoma- unknown) tous polyps in patients in their 50s or 60s). An APC mu- Hyperplastic polyposis syndrome (genetic basis unknown) tation (T to A at nucleotide 3920 or APC I1307K) was found in 6% of Ashkenazi Jews and ∼28% of Ashken- azim with a family history of colorectal cancer (Laken et dreds to thousands of small adenomatous polyps al. 1997). Interestingly, this mutation creates a small hy- throughout the colon. Such polyps typically trace their permutable region, indirectly causing cancer predisposi- emergence to the second decade of life, but have been tion (Laken et al. 1997; Syngal et al. 2000). However, this noted to occur until age 40. Nevertheless, the inevitable mutation has low penetrance in the general population. course is the development of colorectal cancer unless In parallel fashion, often at a feverish pace, the biology this distinctive natural history is interrupted by surgical of the APC protein was unraveled. One critical finding intervention, typically in the form of total proctocolec- related to the premise that nearly 70% of sporadic (aver- tomy with ileoanal anastomosis (that is, removal of the age-risk) colorectal adenomatous polyps harbor somatic colon with anastomosis of the terminal ileum of the APC mutations (Powell et al. 1992). Domains of the APC small bowel with the anal canal via creation of a protein have been dissected and shown to correlate with J-pouch). Certain situations may mandate a subtotal col- functional relationships (Fig. 1). The APC protein, to- ectomy with ileorectal anastomosis, but the rectal gether with glycogen synthase kinase-3␤, phosphory- stump or remnant must be monitored for polyp recur- lates cytoplasmic ␤-catenin, thereby leading to ␤-caten- rence. Extraintestinal manifestations include gastric in’s degradation (Fig. 1; Su et al. 1993; Korinek et al. fundic polyps, small bowel (especially duodenal) adeno- 1997; Morin et al. 1997). Most of the ␤-catenin is bound matous polyps, congenital hypertrophy of the retinal pig- to E-cadherin to facilitate cell–cell contact through the ment epithelium (CHRPE), supernumerary teeth, osteo- adherens junctions (Gumbiner and McCrea 1993). How- mas, cutaneous lipomas and cysts, thyroid tumors, des- ever, germline or somatic APC mutations render cyto- moid tumors, adrenal cortical adenomas, and plasmic ␤-catenin stable, resulting in nuclear transloca- hepatoblastomas. While many of these features are be- tion, where in concert with T-cell factors (TCF), certain nign, FAP patients may develop thyroid cancer, gastric target genes are activated transcriptionally. A partial list adenocarcinoma (<1% lifetime risk), duodenal adenocar- of the target genes is c-myc, cyclin D1,
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