Risks of lynch syndrome cancers for msh6 mutation carriers

Laura Baglietto, Noralane M. Lindor, James G. Dowty, Darren M. White, Anja Wagner, Encarna B. Gomez Garcia, Annette H.J.T. Vriends, Nicola R. Cartwright, Rebecca A. Barnetson, Susan M. Farrington, Albert Tenesa, Heather Hampel, Daniel Buchanan, Sven Arnold, Joanne Young, Michael D. Walsh, Jeremy Jass, Finlay MacRae, Yoland Antill, Ingrid M. WinshipGraham G. Giles, Jack Goldblatt, Susan Parry, Graeme Suthers, Barbara Leggett, Malinda Butz, Melyssa Aronson, Jenny N. Poynter, John A. Baron, Loic Le Marchand, Robert Haile, Steve Gallinger, John L. Hopper, John Potter, Albert De La Chapelle, Hans F. Vasen, Malcolm G. Dunlop, Stephen N. Thibodeau, Mark A. Jenkins

Research output: Contribution to journalArticlepeer-review

257 Scopus citations

Abstract

Background: Germline 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. Methods: We 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. Results: For 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% CI=28% to 62%) for men and 10% (95% CI=5% to 17%) and 20% (95% CI=11% to 35%) for women; for endometrial cancer, 26% (95% CI=18% to 36%) and 44% (95% CI=30% to 58%); and for any cancer associated with Lynch syndrome, 24% (95% CI=16% to 37%) and 47% (95% CI=32% to 66%) for men and 40% (95% CI=32% to 52%) and 65% (95% CI=53% to 78%) for women. Compared with incidence for the general population, MSH6 mutation carriers had an eightfold increased incidence of colorectal cancer (HR=7.6, 95% CI=5.4 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 (HR=25.5, 95% CI=16.8 to 38.7) and a sixfold increased incidence of other cancers associated with Lynch syndrome (HR=6.0, 95% CI=3.4 to 10.7).ConclusionWe have obtained precise and accurate estimates of both absolute and relative cancer risks for MSH6 mutation carriers. The Author 2009. Published by Oxford University Press.2010

Original languageEnglish (US)
Pages (from-to)193-201
Number of pages9
JournalJournal of the National Cancer Institute
Volume102
Issue number3
DOIs
StatePublished - Feb 2010

Bibliographical note

Funding Information:
Recruitment, data collection, and genetic testing for the Colon Cancer Family Registry work were supported by the National Cancer Institute, National Institutes of Health under Request for Applications #CA-95-011, and through cooperative agreements with the members of the Colon Cancer Family Registry and principal investigators. The Columbus-area Hereditary Non-Polyposis Colorectal Cancer study performed by the Ohio State University Comprehensive Cancer Center was supported by grants from the National Cancer Institute, National Institutes of Health (R01-CA67941 and -CA16058). The work in Edinburgh was supported by Cancer Research UK (C348/A8896); a center grant from CORE as part of the Digestive Cancer Campaign (www.corecharity.org.uk); Medical Research Council (G0000657-53203); and Scottish Executive Chief Scientist’s Office (K/OPR/2/2/ D333). National Cancer Institute (CA67941 and CA16058 to A.d.l.c. and H.H).

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