Rationale for, and approach to, studying modifiers of risk in persons with a genetic predisposition to colorectal cancer
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
We address the issue of modifiers of risk for persons who are, on average, at high risk of colorectal cancer due to carrying germline genetic mutations. We discuss how to estimate risk and assess modifiers using data from mutation-carrying families. A critical analytical issue is the adjustment for how families have been sampled (ascertainment). Only a few published studies have made appropriate adjustments and have mostly reported lifetime risks of less than 50%. Incomplete penetrance and differences in risk by subcategories are consistent with the existence of genetic and/or environmental risk modifiers. Data from large cohorts of carriers are required to study such modifiers with precision.
- Last JM, ed.: A Dictionary of Epidemiology, 4th edn. New York: Oxford University; 2001.
- 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, 96:261–268. CrossRef
- 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. Gastroenterol 1999, 116:1453–1456. CrossRef
- Lynch HT, Kimberling W, Albano WA, et al.: Hereditary nonpolyposis colorectal cancer (Lynch syndromes I and II). Clinical description and resource. Cancer 1985, 56:934–938. CrossRef
- Southey MC, Jenkins MA, Mead L, et al.: Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer. J Clin Oncol 2005, 23:6524–6532. CrossRef
- Hopper JL: Application of genetics to the prevention of colorectal cancer. Recent Results Cancer Res 2005, 166:17–33.
- Lenz H-J: First Amsterdam, then Bethesda, now Melbourne? J Clin Oncol 2005, 23:6445–6449. CrossRef
- Hopper JL, Southey MC, Dite GS, et al.: Population-based estimate of the average age-specific cumulative risk of breast cancer for a defined set of protein-truncating mutations in BRCA1 and BRCA2. Australian Breast Cancer Family Study. Cancer Epidemiol Biomarkers Prev 1999, 8:741–747.
- Hopper JL, Bishop DT, Easton DF: Population-based family studies in genetic epidemiology. Lancet 2005, 366:1397–1406. CrossRef
- Froggatt NJ, Brassett C, Koch DJ, et al.: Mutation screening of MSH2 and MLH1 mRNA in hereditary non-polyposis colon cancer syndrome. J Med Genet 1996, 33:726–730. CrossRef
- Vasen HF, Wijnen JT, Menko FH, et al.: Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gatroenterology 1996, 110:1020–1027. CrossRef
- Heinimann K, Muller H, Weber W, Scott RJ: Disease expression in Swiss hereditary non-polyposis colorectal cancer (HNPCC) kindreds. Int J Cancer 1997, 74:281–285. CrossRef
- Pensotti V, Radice P, Presciuttini S, et al.: Mean age of tumor onset in hereditary nonpolyposis colorectal cancer (HNPCC) families correlates with the presence of mutations in DNA mismatch repair genes. Genes Chromosomes Cancer 1997, 19:135–142. CrossRef
- Aarnio M, Sankila R, Pukkala E, et al.: Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 1999, 81:214–218. CrossRef
- Vasen HF, Stormorken A, Menko FH, et al.: MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: a study of hereditary nonpolyposis colorectal cancer families. J Clin Oncol 2001, 19:4074–4080.
- de Vos tot Nederveen Cappel WH, Nagengast FM, Griffioen G, et al.: Surveillance for hereditary nonpolyposis colorectal cancer: a long-term study on 114 families. Dis Colon Rectum 2002, 45:1588–1594. CrossRef
- Green J, O’Driscoll M, Barnes A, et al.: Impact of gender and parent of origin on the phenotypic expression of hereditary nonpolyposis colorectal cancer in a large Newfoundland kindred with a common MSH2 mutation. Dis Colon Rectum 2002, 45:1223–1232. CrossRef
- Easton DF, Hopper JL, Thomas DC, et al.: Breast cancer risks for BRCA1/2 carriers. Science 2004, 306:2187–2191. CrossRef
- Carayol J, Khlat M, Maccario J, Bonaiti-Pellie C: Hereditary non-polyposis colorectal cancer: current risks of colorectal cancer largely overestimated. J Med Genet 2002, 39:335–339. CrossRef
- Quehenberger F, Vasen HFA, van Houwelingen HC: Risk of colorectal and endometrial cancer for carriers of mutations of the hMLH1 and hMSH2 gene: correction for ascertainment. J Med Genet 2005, 42:491–496. CrossRef
- Mitchell RJ, Farrington SM, Dunlop MG, Campbell H: Mismatch repair genes hMLH1 and hMSH2 and colorectal cancer: a HuGE review. Am J Epidemiol 2002, 156:885–902. CrossRef
- Dunlop MG, Farrington SM, Carothers AD, et al.: Cancer risk associated with germline DNA mismatch repair gene mutations. Hum Mol Genet 1997, 6:105–110. CrossRef
- Jenkins MA, Baglietto L, Dowty JG, et al.: Cancer risks for carriers of germline mutations in hMLH1, hMSH2, hMSH6 and hPMS2: a population-based early-onset case-family study. Clin Gastroenterol Hepatol 2006, 4:489–498. CrossRef
- Buttin BM, Powell MA, Mutch DG, et al.: Penetrance and expressivity of MSH6 germline mutations in seven kindreds not ascertained by family history. Am J Hum Genet 2004, 74:1262–1269. CrossRef
- 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, 354:2751–2763 CrossRef
- 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, 293:1979–1985. CrossRef
- Rationale for, and approach to, studying modifiers of risk in persons with a genetic predisposition to colorectal cancer
Current Oncology Reports
Volume 9, Issue 3 , pp 202-207
- Cover Date
- Print ISSN
- Online ISSN
- Current Science Inc.
- Additional Links