Colorectal and Other Cancer Risks for Carriers and Noncarriers From Families With a DNA Mismatch Repair Gene Mutation: A Prospective Cohort Study.

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Aung Ko Win, Graham G. Giles, Ingrid Winship, Melissa C. Southey, John L. Hopper, and Mark A. Jenkins, The University of Melbourne;Ingrid Winship and Finlay A. Macrae, The Royal Melbourne Hospital, Parkville; Graham G. Giles, Cancer Epidemiology Centre, Cancer CouncilVictoria, Carlton, Victoria; Joanne P. Young, Daniel D. Buchanan, and Mark Clendenning, Queensland Institute of Medical Research; Joanne P.Young, School of Medicine, University of Queensland, Herston, Queensland; Katherine M. Tucker, Hereditary Cancer Clinic, Prince of WalesHospital, Randwick, New South Wales; Graeme P. Young, Flinders Centre for Cancer Prevention and Control, Flinders University, Adelaide,South Australia; Jack Goldblatt, Genetic Services of Western Australia and School of Paediatrics and Child Health, University of WesternAustralia, Perth, Australia; Julie Arnold, New Zealand Familial Gastrointestinal Cancer Registry, Auckland City Hospital, Auckland, NewZealand; Bharati Bapat and Steven Gallinger, Samuel Lunenfeld Research Institute, Mount Sinai Hospital; Bharati Bapat, University of Toronto;Steven Gallinger, Cancer Care Ontario, Toronto, Ontario, Canada; Noralane M. Lindor, Stephen N. Thibodeau, and Shanaka R. Gunawardena,Mayo Clinic, Rochester, MN; Dennis J. Ahnen, Denver Veterans Affairs Medical Center, School of Medicine, University of Colorado, Denver,CO; John A. Baron, University of North Carolina, Chapel Hill, NC; Graham Casey and Robert W. Haile, University of Southern California, LosAngeles, CA; Loïc Le Marchand, University of Hawaii Cancer Center, Honolulu, HI; and Polly A. Newcomb, Fred Hutchinson Cancer ResearchCenter, Seattle, WA.

Abstract

PURPOSETo determine whether cancer risks for carriers and noncarriers from families with a mismatch repair (MMR) gene mutation are increased above the risks of the general population. PATIENTS AND METHODSWe prospectively followed a cohort of 446 unaffected carriers of an MMR gene mutation (MLH1, n = 161; MSH2, n = 222; MSH6, n = 47; and PMS2, n = 16) and 1,029 their unaffected relatives who did not carry a mutation every 5 years at recruitment centers of the Colon Cancer Family Registry. For comparison of cancer risk with the general population, we estimated country-, age-, and sex-specific standardized incidence ratios (SIRs) of cancer for carriers and noncarriers.ResultsOver a median follow-up of 5 years, mutation carriers had an increased risk of colorectal cancer (CRC; SIR, 20.48; 95% CI, 11.71 to 33.27; P < .001), endometrial cancer (SIR, 30.62; 95% CI, 11.24 to 66.64; P < .001), ovarian cancer (SIR, 18.81; 95% CI, 3.88 to 54.95; P < .001), renal cancer (SIR, 11.22; 95% CI, 2.31 to 32.79; P < .001), pancreatic cancer (SIR, 10.68; 95% CI, 2.68 to 47.70; P = .001), gastric cancer (SIR, 9.78; 95% CI, 1.18 to 35.30; P = .009), urinary bladder cancer (SIR, 9.51; 95% CI, 1.15 to 34.37; P = .009), and female breast cancer (SIR, 3.95; 95% CI, 1.59 to 8.13; P = .001). We found no evidence of their noncarrier relatives having an increased risk of any cancer, including CRC (SIR, 1.02; 95% CI, 0.33 to 2.39; P = .97). CONCLUSIONWe confirmed that carriers of an MMR gene mutation were at increased risk of a wide variety of cancers, including some cancers not previously recognized as being a result of MMR mutations, and found no evidence of an increased risk of cancer for their noncarrier relatives.