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Risks of Lynch Syndrome Cancers for MSH6 Mutation Carriers

Risks of Lynch Syndrome Cancers for MSH6 Mutation Carriers BackgroundGermline mutations in MSH6 account for 10%20% of Lynch syndrome colorectal cancers caused by hereditary DNA mismatch repair gene mutations. Because there have been only a few studies of mutation carriers, their cancer risks are uncertain.MethodsWe identified 113 families of MSH6 mutation carriers from five countries that we ascertained through family cancer clinics and population-based cancer registries. Mutation status, sex, age, and histories of cancer, polypectomy, and hysterectomy were sought from 3104 of their relatives. Age-specific cumulative risks for carriers and hazard ratios (HRs) for cancer risks of carriers, compared with those of the general population of the same country, were estimated by use of a modified segregation analysis with appropriate conditioning depending on ascertainment.ResultsFor MSH6 mutation carriers, the estimated cumulative risks to ages 70 and 80 years, respectively, were as follows: for colorectal cancer, 22% (95% confidence interval [CI]14% to 32%) and 44% (95% CI28% to 62%) for men and 10% (95% CI5% to 17%) and 20% (95% CI11% to 35%) for women; for endometrial cancer, 26% (95% CI18% to 36%) and 44% (95% CI30% to 58%); and for any cancer associated with Lynch syndrome, 24% (95% CI16% to 37%) and 47% (95% CI32% to 66%) for men and 40% (95% CI32% to 52%) and 65% (95% CI53% to 78%) for women. Compared with incidence for the general population, MSH6 mutation carriers had an eightfold increased incidence of colorectal cancer (HR7.6, 95% CI5.4 to 10.8), which was independent of sex and age. Women who were MSH6 mutation carriers had a 26-fold increased incidence of endometrial cancer (HR25.5, 95% CI16.8 to 38.7) and a sixfold increased incidence of other cancers associated with Lynch syndrome (HR6.0, 95% CI3.4 to 10.7).ConclusionWe have obtained precise and accurate estimates of both absolute and relative cancer risks for MSH6 mutation carriers. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JNCI: Journal of the National Cancer Institute Oxford University Press

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References (79)

Publisher
Oxford University Press
Copyright
The Author 2009. Published by Oxford University Press.
ISSN
0027-8874
eISSN
1460-2105
DOI
10.1093/jnci/djp473
pmid
20028993
Publisher site
See Article on Publisher Site

Abstract

BackgroundGermline mutations in MSH6 account for 10%20% of Lynch syndrome colorectal cancers caused by hereditary DNA mismatch repair gene mutations. Because there have been only a few studies of mutation carriers, their cancer risks are uncertain.MethodsWe identified 113 families of MSH6 mutation carriers from five countries that we ascertained through family cancer clinics and population-based cancer registries. Mutation status, sex, age, and histories of cancer, polypectomy, and hysterectomy were sought from 3104 of their relatives. Age-specific cumulative risks for carriers and hazard ratios (HRs) for cancer risks of carriers, compared with those of the general population of the same country, were estimated by use of a modified segregation analysis with appropriate conditioning depending on ascertainment.ResultsFor MSH6 mutation carriers, the estimated cumulative risks to ages 70 and 80 years, respectively, were as follows: for colorectal cancer, 22% (95% confidence interval [CI]14% to 32%) and 44% (95% CI28% to 62%) for men and 10% (95% CI5% to 17%) and 20% (95% CI11% to 35%) for women; for endometrial cancer, 26% (95% CI18% to 36%) and 44% (95% CI30% to 58%); and for any cancer associated with Lynch syndrome, 24% (95% CI16% to 37%) and 47% (95% CI32% to 66%) for men and 40% (95% CI32% to 52%) and 65% (95% CI53% to 78%) for women. Compared with incidence for the general population, MSH6 mutation carriers had an eightfold increased incidence of colorectal cancer (HR7.6, 95% CI5.4 to 10.8), which was independent of sex and age. Women who were MSH6 mutation carriers had a 26-fold increased incidence of endometrial cancer (HR25.5, 95% CI16.8 to 38.7) and a sixfold increased incidence of other cancers associated with Lynch syndrome (HR6.0, 95% CI3.4 to 10.7).ConclusionWe have obtained precise and accurate estimates of both absolute and relative cancer risks for MSH6 mutation carriers.

Journal

JNCI: Journal of the National Cancer InstituteOxford University Press

Published: Feb 3, 2010

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