Combined analysis of three Lynch syndrome cohorts confirms the modifying effects of 8q23.3 and 11q23.1 in MLH1 mutation carriers

Int J Cancer. 2013 Apr 1;132(7):1556-64. doi: 10.1002/ijc.27843. Epub 2012 Oct 11.


Two colorectal cancer (CRC) susceptibility loci have been found to be significantly associated with an increased risk of CRC in Dutch Lynch syndrome (LS) patients. Recently, in a combined study of Australian and Polish LS patients, only MLH1 mutation carriers were found to be at increased risk of disease. A combined analysis of the three data-sets was performed to better define this association. This cohort-study includes three sample populations combined totaling 1,352 individuals from 424 families with a molecular diagnosis of LS. Seven SNPs, from six different CRC susceptibility loci, were genotyped by both research groups and the data analyzed collectively. We identified associations at two of the six CRC susceptibility loci in MLH1 mutation carriers from the combined LS cohort: 11q23.1 (rs3802842, HR = 2.68, p ≤ 0.0001) increasing risk of CRC, and rs3802842 in a pair-wise combination with 8q23.3 (rs16892766) affecting age of diagnosis of CRC (log-rank test; p ≤ 0.0001). A significant difference in the age of diagnosis of CRC of 28 years was observed in individuals carrying three risk alleles compared to those with 0 risk alleles for the pair-wise SNP combination. A trend (due to significance threshold of p ≤ 0.0010) was observed in MLH1 mutation carriers towards an increased risk of CRC for the pair-wise combination (p = 0.002). This study confirms the role of modifier loci in LS. We consider that LS patients with MLH1 mutations would greatly benefit from additional genotyping of SNPs rs3802842 and rs16892766 for personalized risk assessment and a tailored surveillance program.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Chromosomes, Human, Pair 11 / genetics*
  • Chromosomes, Human, Pair 8 / genetics*
  • Cohort Studies
  • Colorectal Neoplasms / etiology*
  • Colorectal Neoplasms / pathology
  • Colorectal Neoplasms, Hereditary Nonpolyposis / complications
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / mortality
  • Female
  • Follow-Up Studies
  • Genes, Modifier / genetics
  • Genetic Predisposition to Disease*
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • MutL Protein Homolog 1
  • Mutation / genetics*
  • Nuclear Proteins / genetics*
  • Polymorphism, Single Nucleotide / genetics
  • Precision Medicine
  • Prognosis
  • Risk Factors
  • Survival Rate


  • Adaptor Proteins, Signal Transducing
  • MLH1 protein, human
  • Nuclear Proteins
  • MutL Protein Homolog 1