Are the common genetic variants associated with colorectal cancer risk for DNA mismatch repair gene mutation carriers?

Aung Ko Win, John Hopper, Daniel Buchanan, Joanne Young, Albert Tenesa, J Dowty, Graham Giles, Jack Goldblatt, Ingrid Winship, Alex Boussioutas, Graeme Young, Susan Parry, John Baron, David Duggan, Steven Gallinger, Polly Newcomb, Robert Haile, Loic Le Marchand, N Lindor, Mark Jenkins

    Research output: Contribution to journalArticlepeer-review

    30 Citations (Scopus)


    Background: Genome-wide association studies have identified at least 15 independent common genetic variants associated with colorectal cancer (CRC) risk. The aim of this study was to investigate whether 11 of these variants are associated with CRC risk for carriers of germline mutations in DNA mismatch repair (MMR) genes. Methods: A total of 927 MMR gene mutation carriers (360 MLH1, 442 MSH2, 85 MSH6 and 40 PMS2) from 315 families enrolled in the Colon Cancer Family Registry, were genotyped for the single nucleotide polymorphisms (SNPs): rs16892766 (8q23.3), rs6983267 (8q24.21), rs719725 (9p24), rs10795668 (10p14), rs3802842 (11q23.1), rs4444235 (14q22.2), rs4779584 (15q13.3), rs9929218 (16q22.1), rs4939827 (18q21.1), rs10411210 (19q13.1) and rs961253 (20p12.3). We used a weighted Cox regression to estimate CRC risk for homozygous and heterozygous carriers of the risk allele compared with homozygous non-carriers as well as for an additive per allele model (on the log scale). Results: Over a total of 40,978 person-years observation, 426 (46%) carriers were diagnosed with CRC at a mean age of 44.3 years. For all carriers combined, we found no evidence of an association between CRC risk and the total number of risk alleles (hazard ratio [HR] per risk allele = 0.97, 95% confidence interval [CI] = 0.88-1.07, p = 0.52). Conclusions: We found no evidence that the SNPs associated with CRC in the general population are modifiers of the risk for MMR gene mutation carriers overall, and therefore any evidence of proven clinical utility in Lynch syndrome.

    Original languageEnglish
    Pages (from-to)1578-1587
    Number of pages10
    JournalEuropean Journal of Cancer
    Issue number7
    Publication statusPublished - May 2013


    • Colorectal cancer
    • Genetic variant
    • Lynch syndrome
    • Mismatch repair


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