Dependence of colorectal cancer risk on the parent-of-origin of mutations in DNA mismatch repair genes

van Vliet, Christine M., Dowty, James G., van Vliet, Jane L., Smith, Letitia, Mead, Leeanne J., Macrae, Finlay A., St John, D. James B., Giles, Graham G., Southey, Melissa C., Jenkins, Mark A., Velan, Gary M., and Hopper, John L. (2011) Dependence of colorectal cancer risk on the parent-of-origin of mutations in DNA mismatch repair genes. Human Mutation, 32 (2). pp. 207-212.

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Genetic diseases associated with dynamic mutations in microsatellite DNA often display parent-of-origin effects (POEs) in which the risk of disease depends on the sex of the parent from whom the disease allele was inherited. Carriers of germline mutations in mismatch repair (MMR) genes have high risks of colorectal carcinoma (CRC). We investigated whether these risks depend on the parent-of-origin of the mutation. We studied 422 subjects, including 89 MMR gene mutation carriers, from 17 population-based families who were each recruited via a CRC case diagnosed before age 45 years and found to carry a MMR gene mutation. The POE hazard ratio (HRPOE), defined to be the CRC incidence for carriers with maternally derived mutations divided by the corresponding paternal incidence, was estimated using a novel application of modified segregation analysis. HRPOE (95% confidence interval) was estimated to be 3.2 (1.1–9.8) for males (P = 0.03) and 0.8 (0.2–2.8) for females (P = 0.5) and the corresponding cumulative risks to age 80 years were 88% (54%–100%) for male carriers with maternally derived mutations and 38–48% for all other carriers. If confirmed by larger studies, these results will have important implications for the etiology of CRC and for the clinical management of MMR gene mutation carriers.

Item ID: 35573
Item Type: Article (Research - C1)
ISSN: 1098-1004
Keywords: Lynch syndrome, HNPCC, colorectal cancer, mismatch repair, MMR, parent-of-origin, POE, penetrance, segregation analysis, maximum likelihood
Funders: Victorian Health Promotion Foundation, Australian National Health and Medical Research Council (NHMRC)
Date Deposited: 01 Oct 2014 15:51
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1112 Oncology and Carcinogenesis > 111203 Cancer Genetics @ 50%
11 MEDICAL AND HEALTH SCIENCES > 1117 Public Health and Health Services > 111706 Epidemiology @ 50%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920102 Cancer and Related Disorders @ 100%
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