Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study

Aung Ko Win, Joanne Young, Noralane Lindor, Katherine Tucker, Dennis Ahnen, Graeme Young, Daniel Buchanan, Mark Clendenning, Graham Giles, Ingrid Winship, F Macrae, Jack Goldblatt, M Southey, Julie Arnold, S Thibodeau, Shanaka Gunawardena, Bharati Bapat, John Baron, Graham Casey, Steven GallingerLoic Le Marchand, Polly Newcomb, Robert Haile, John Hopper, Mark Jenkins

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    211 Citations (Scopus)

    Abstract

    Purpose: To 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 Methods: We 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. Results: Over 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). Conclusion: We 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.

    Original languageEnglish
    Pages (from-to)958-964
    Number of pages7
    JournalJournal of Clinical Oncology
    Volume30
    Issue number9
    DOIs
    Publication statusPublished - 2012

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    Win, A. K., Young, J., Lindor, N., Tucker, K., Ahnen, D., Young, G., Buchanan, D., Clendenning, M., Giles, G., Winship, I., Macrae, F., Goldblatt, J., Southey, M., Arnold, J., Thibodeau, S., Gunawardena, S., Bapat, B., Baron, J., Casey, G., ... Jenkins, M. (2012). Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. Journal of Clinical Oncology, 30(9), 958-964. https://doi.org/10.1200/JCO.2011.39.5590