Cancer risks for MLH1 and MSH2 mutation carriers

J Dowty, Aung Ko Win, Daniel Buchanan, N Lindor, Finlay Macrae, Mark Clendenning, Yoland Antill, S Thibodeau, Graham Casey, Steven Gallinger, Loic Le Marchand, Polly Newcomb, Robert Haile, Graeme Young, Paul James, Graham Giles, Shanaka Gunawardena, Barbara Leggett, Michael Gattas, Alex BoussioutasD Ahnen, John Baron, Susan Parry, Jack Goldblatt, Joanne Young, John Hopper, Mark Jenkins

    Research output: Contribution to journalArticle

    135 Citations (Scopus)

    Abstract

    We studied 17,576 members of 166 MLH1 and 224 MSH2 mutation-carrying families from the Colon Cancer Family Registry. Average cumulative risks of colorectal cancer (CRC), endometrial cancer (EC), and other cancers for carriers were estimated using modified segregation analysis conditioned on ascertainment criteria. Heterogeneity in risks was investigated using a polygenic risk modifier. Average CRC cumulative risks at the age of 70 years (95% confidence intervals) for MLH1 and MSH2 mutation carriers, respectively, were estimated to be 34% (25%-50%) and 47% (36%-60%) for male carriers and 36% (25%-51%) and 37% (27%-50%) for female carriers. Corresponding EC risks were 18% (9.1%-34%) and 30% (18%-45%). A high level of CRC risk heterogeneity was observed (P < 0.001), with cumulative risks at the age of 70 years estimated to follow U-shaped distributions. For example, 17% of male MSH2 mutation carriers have estimated lifetime risks of 0%-10% and 18% have risks of 90%-100%. Therefore, average risks are similar for the two genes but there is so much individual variation about the average that large proportions of carriers have either very low or very high lifetime cancer risks. Our estimates of CRC and EC cumulative risks for MLH1 and MSH2 mutation carriers are the most precise currently available.

    Original languageEnglish
    Pages (from-to)490-497
    Number of pages8
    JournalHuman Mutation
    Volume34
    Issue number3
    DOIs
    Publication statusPublished - Mar 2013

    Keywords

    • Cancer
    • Colon CFR
    • Colorectal cancer
    • Endometrial cancer
    • Lynch syndrome
    • MLH1
    • MSH2
    • Penetrance
    • Risk
    • Segregation analysis

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  • Cite this

    Dowty, J., Win, A. K., Buchanan, D., Lindor, N., Macrae, F., Clendenning, M., Antill, Y., Thibodeau, S., Casey, G., Gallinger, S., Le Marchand, L., Newcomb, P., Haile, R., Young, G., James, P., Giles, G., Gunawardena, S., Leggett, B., Gattas, M., ... Jenkins, M. (2013). Cancer risks for MLH1 and MSH2 mutation carriers. Human Mutation, 34(3), 490-497. https://doi.org/10.1002/humu.22262