Familial Colorectal Cancer: Understanding the Alphabet Soup

Abstract

While most colorectal cancers (CRCs) originate from nonhereditary spontaneous mutations, one-third of cases are familial or hereditary. Hereditary CRCs, which account for < 5% of all CRCs, have identifiable germline mutations and phenotypes, such as Lynch syndrome and familial adenomatous polyposis (FAP). Familial CRCs, which account for up to 30% of CRCs, have no identifiable germline mutation or specific pattern of inheritance, but higher-than-expected incidence within a family. Since the discovery that certain genotypes can lead to development of CRC, thousands of mutations have now been implicated in CRC. These new findings have enhanced our ability to identify at-risk patients, initiate better surveillance, and take preventative measures. Given the large number of genes now associated with hereditary and familial CRCs, clinicians should be familiar with the alphabet soup of genes to provide the highest quality of care for patients and families.

Keywords

colorectal cancer - hereditary - familial - genetic

• References

• 1 National Cancer Institute. SEER stat fact sheets: colon and rectum cancer. Available at: http://seer.cancer.gov/statfacts/html/colorect.html . Accessed August 20, 2015
• 2 Bodmer WF, Bailey CJ, Bodmer J , et al. Localization of the gene for familial adenomatous polyposis on chromosome 5. Nature 1987; 328 (6131) 614-616
• 3 Nagy R, Sweet K, Eng C. Highly penetrant hereditary cancer syndromes. Oncogene 2004; 23 (38) 6445-6470
• 4 Lynch HT, Shaw MW, Magnuson CW, Larsen AL, Krush AJ. Hereditary factors in cancer. Study of two large midwestern kindreds. Arch Intern Med 1966; 117 (2) 206-212
• 5 Fishel R, Lescoe MK, Rao MR , et al. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 1993; 75 (5) 1027-1038
• 6 Aarnio M, Mecklin JP, Aaltonen LA, Nyström-Lahti M, Järvinen HJ. Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer 1995; 64 (6) 430-433
• 7 Charames GS, Bapat B. Genomic instability and cancer. Curr Mol Med 2003; 3 (7) 589-596
• 8 Jacob S, Praz F. DNA mismatch repair defects: role in colorectal carcinogenesis. Biochimie 2002; 84 (1) 27-47
• 9 Vasen HF, Mecklin JP, Khan PM, Lynch HT. The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum 1991; 34 (5) 424-425
• 10 Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 1999; 116 (6) 1453-1456
• 11 Umar A, Boland CR, Terdiman JP , et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 2004; 96 (4) 261-268
• 12 Barzi A, Sadeghi S, Kattan MW, Meropol NJ. Comparative effectiveness of screening strategies for Lynch syndrome. J Natl Cancer Inst 2015; 107 (4)
• 13 Barnetson RA, Tenesa A, Farrington SM , et al. Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. N Engl J Med 2006; 354 (26) 2751-2763
• 14 Chen S, Wang W, Lee S , et al; Colon Cancer Family Registry. Prediction of germline mutations and cancer risk in the Lynch syndrome. JAMA 2006; 296 (12) 1479-1487
• 15 Kastrinos F, Steyerberg EW, Mercado R , et al. The PREMM(1,2,6) model predicts risk of MLH1, MSH2, and MSH6 germline mutations based on cancer history. Gastroenterology 2011; 140 (1) 73-81
• 16 Green RC, Parfrey PS, Woods MO, Younghusband HB. Prediction of Lynch syndrome in consecutive patients with colorectal cancer. J Natl Cancer Inst 2009; 101 (5) 331-340
• 17 Järvinen HJ, Aarnio M, Mustonen H , et al. Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 2000; 118 (5) 829-834
• 18 Vasen HF, Taal BG, Nagengast FM , et al. Hereditary nonpolyposis colorectal cancer: results of long-term surveillance in 50 families. Eur J Cancer 1995; 31A (7–8) 1145-1148
• 19 National Comprehensive Cancer Network Genetic/familial high-risk assessment: colorectal (2015); version 1.2015. Available at: http://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf . Accessed August 20, 2015
• 20 Fitzgibbons Jr RJ, Lynch HT, Stanislav GV , et al. Recognition and treatment of patients with hereditary nonpolyposis colon cancer (Lynch syndromes I and II). Ann Surg 1987; 206 (3) 289-295
• 21 Wennstrom J, Pierce ER, McKusick VA. Hereditary benign and malignant lesions of the large bowel. Cancer 1974; 34 (3) 850-857
• 22 Bisgaard ML, Fenger K, Bülow S, Niebuhr E, Mohr J. Familial adenomatous polyposis (FAP): frequency, penetrance, and mutation rate. Hum Mutat 1994; 3 (2) 121-125
• 23 Leoz ML, Carballal S, Moreira L, Ocaña T, Balaguer F. The genetic basis of familial adenomatous polyposis and its implications for clinical practice and risk management. Appl Clin Genet 2015; 8: 95-107
• 24 Esplin ED, Snyder MP. Genomic era diagnosis and management of hereditary and sporadic colon cancer. World J Clin Oncol 2014; 5 (5) 1036-1047
• 25 Ellis CN. Colonic adenomatous polyposis syndromes: clinical management. Clin Colon Rectal Surg 2008; 21 (4) 256-262
• 26 Laurent-Puig P, Béroud C, Soussi T. APC gene: database of germline and somatic mutations in human tumors and cell lines. Nucleic Acids Res 1998; 26 (1) 269-270
• 27 Fodde R. The APC gene in colorectal cancer. Eur J Cancer 2002; 38 (7) 867-871
• 28 Winawer S, Fletcher R, Rex D , et al; Gastrointestinal Consortium Panel. Colorectal cancer screening and surveillance: clinical guidelines and rationale-Update based on new evidence. Gastroenterology 2003; 124 (2) 544-560
• 29 Kwong LN, Dove WF. APC and its modifiers in colon cancer. Adv Exp Med Biol 2009; 656: 85-106
• 30 Campos FG, Sulbaran M, Safatle-Ribeiro AV, Martinez CA. Duodenal adenoma surveillance in patients with familial adenomatous polyposis. World J Gastrointest Endosc 2015; 7 (10) 950-959
• 31 Heiskanen I, Kellokumpu I, Järvinen H. Management of duodenal adenomas in 98 patients with familial adenomatous polyposis. Endoscopy 1999; 31 (6) 412-416
• 32 Church J. Ileoanal pouch neoplasia in familial adenomatous polyposis: an underestimated threat. Dis Colon Rectum 2005; 48 (9) 1708-1713
• 33 Jasperson KW, Tuohy TM, Neklason DW, Burt RW. Hereditary and familial colon cancer. Gastroenterology 2010; 138 (6) 2044-2058
• 34 Sampson JR, Jones N. MUTYH-associated polyposis. Best Pract Res Clin Gastroenterol 2009; 23 (2) 209-218
• 35 Ricci MT, Salemme M, Villanacci V, Varesco L. The genetics of inherited predispositions to colorectal polyps: a quick guide for clinicians. Colorectal Dis 2015; 17 (Suppl. 01) 3-9
• 36 Al-Tassan N, Chmiel NH, Maynard J , et al. Inherited variants of MYH associated with somatic G:C—>T:A mutations in colorectal tumors. Nat Genet 2002; 30 (2) 227-232
• 37 de Ferro SM, Suspiro A, Fidalgo P , et al. Aggressive phenotype of MYH-associated polyposis with jejunal cancer and intra-abdominal desmoid tumor: report of a case. Dis Colon Rectum 2009; 52 (4) 742-745
• 38 Terdiman JP. MYH-associated disease: attenuated adenomatous polyposis of the colon is only part of the story. Gastroenterology 2009; 137 (6) 1883-1886
• 39 Boparai KS, Dekker E, Van Eeden S , et al. Hyperplastic polyps and sessile serrated adenomas as a phenotypic expression of MYH-associated polyposis. Gastroenterology 2008; 135 (6) 2014-2018
• 40 Nielsen M, Joerink-van de Beld MC, Jones N , et al. Analysis of MUTYH genotypes and colorectal phenotypes in patients With MUTYH-associated polyposis. Gastroenterology 2009; 136 (2) 471-476
• 41 Church JM. Polymerase proofreading-associated polyposis: a new, dominantly inherited syndrome of hereditary colorectal cancer predisposition. Dis Colon Rectum 2014; 57 (3) 396-397
• 42 Gallione C, Aylsworth AS, Beis J , et al. Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome. Am J Med Genet A 2010; 152A (2) 333-339
• 43 Zhou XP, Woodford-Richens K, Lehtonen R , et al. Germline mutations in BMPR1A/ALK3 cause a subset of cases of juvenile polyposis syndrome and of Cowden and Bannayan-Riley-Ruvalcaba syndromes. Am J Hum Genet 2001; 69 (4) 704-711
• 44 Calva D, Howe JR. Hamartomatous polyposis syndromes. Surg Clin North Am 2008; 88 (4) 779-817 , vii
• 45 Howe JR, Mitros FA, Summers RW. The risk of gastrointestinal carcinoma in familial juvenile polyposis. Ann Surg Oncol 1998; 5 (8) 751-756
• 46 McGarrity TJ, Kulin HE, Zaino RJ. Peutz-Jeghers syndrome. Am J Gastroenterol 2000; 95 (3) 596-604
• 47 Gruber SB, Entius MM, Petersen GM , et al. Pathogenesis of adenocarcinoma in Peutz-Jeghers syndrome. Cancer Res 1998; 58 (23) 5267-5270
• 48 Oncel M, Remzi FH, Church JM, Connor JT, Fazio VW. Benefits of ‘clean sweep’ in Peutz-Jeghers patients. Colorectal Dis 2004; 6 (5) 332-335
• 49 Kopácová M, Bures J, Ferko A, Tachecí I, Rejchrt S. Comparison of intraoperative enteroscopy and double-balloon enteroscopy for the diagnosis and treatment of Peutz-Jeghers syndrome. Surg Endosc 2010; 24 (8) 1904-1910
• 50 Murday V, Slack J. Inherited disorders associated with colorectal cancer. Cancer Surv 1989; 8 (1) 139-157
• 51 Stambolic V, Suzuki A, de la Pompa JL , et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 1998; 95 (1) 29-39
• 52 Cho YJ, Liang P. Killin is a p53-regulated nuclear inhibitor of DNA synthesis. Proc Natl Acad Sci U S A 2008; 105 (14) 5396-5401
• 53 Church J. The ASCRS Textbook of Colon and Rectal Surgery. 2nd ed. Berlin, Germany: Springer Science + Business Media; 2011
• 54 Hawkins NJ, Gorman P, Tomlinson IP, Bullpitt P, Ward RL. Colorectal carcinomas arising in the hyperplastic polyposis syndrome progress through the chromosomal instability pathway. Am J Pathol 2000; 157 (2) 385-392
• 55 Lindor NM, Rabe K, Petersen GM , et al. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA 2005; 293 (16) 1979-1985
• 56 Carethers JM, Stoffel EM. Lynch syndrome and Lynch syndrome mimics: The growing complex landscape of hereditary colon cancer. World J Gastroenterol 2015; 21 (31) 9253-9261
• 57 Johns LE, Houlston RS. A systematic review and meta-analysis of familial colorectal cancer risk. Am J Gastroenterol 2001; 96 (10) 2992-3003
• 58 Tenesa A, Dunlop MG. New insights into the aetiology of colorectal cancer from genome-wide association studies. Nat Rev Genet 2009; 10 (6) 353-358
• 59 National Human Genome Research Institute. Genome-wide association studies (2015). Available at: https://www.genome.gov/20019523 . Accessed August 31, 2015
• 60 Win AK, Macinnis RJ, Hopper JL, Jenkins MA. Risk prediction models for colorectal cancer: a review. Cancer Epidemiol Biomarkers Prev 2012; 21 (3) 398-410
• 61 Kalady MF, Church JM. Prophylactic colectomy: Rationale, indications, and approach. J Surg Oncol 2015; 111 (1) 112-117