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Dependence of colorectal cancer risk on the parent‐of‐origin of mutations in DNA mismatch repair genes
Author(s) -
van Vliet Christine M.,
Dowty James G.,
van Vliet Jane L.,
Smith Letitia,
Mead Leeanne J.,
Macrae Finlay A.,
John D. James B. St.,
Giles Graham G.,
Southey Melissa C.,
Jenkins Mark A.,
Velan Gary M.,
Hopper John L.
Publication year - 2011
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21408
Subject(s) - biology , dna mismatch repair , genetics , lynch syndrome , germline mutation , allele , colorectal cancer , mutation , population , cancer , gene , medicine , environmental health
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 (HR POE ), 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. HR POE (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.Hum Mutat 32: 1‐6, 2011. © 2011 Wiley‐Liss, Inc.