Evidence for Heritable Predisposition to Epigenetic Silencing of MLH1

Int J Cancer. 2007 Apr 15;120(8):1684-8. doi: 10.1002/ijc.22406.


Epigenetic silencing of MLH1 is the most common cause of defective DNA mismatch repair in endometrial and colorectal cancers. We hypothesized that variation in the MLH1 gene might contribute to the risk for MLH1 methylation and epigenetic silencing. We undertook a case-control study to test for the association between MLH1 variants and abnormal MLH1 methylation. Eight MLH1 SNPs were typed in the normal DNA from women with endometrial carcinoma. For these studies, the cases were women whose cancers exhibited MLH1 methylation (N = 98) and the controls were women whose cancers had no MLH1 methylation (N = 219). One MLH1 SNP, rs1800734, located in the MLH1 CpG island at -93 from the translation start site, was significantly associated with MLH1 methylation as were age at diagnosis and patient body mass index. In validation experiments, a similar-sized cohort of colorectal carcinoma patients (N = 387) showed a similar degree of association with the -93 SNP; a smaller cohort of endometrial carcinomas (N = 181) showed no association. Combining all 3 cohorts showed an odds ratio of 1.61 (95% CI: 1.20-2.16) for the AA or AG vs. GG genotype at the -93 SNP. Identification of risk alleles for MLH1 methylation could shed light on mechanisms of epigenetic silencing and may ultimately lead to new approaches to the prevention or treatment of malignancies associated with MLH1 inactivation.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adult
  • Aged
  • Aged, 80 and over
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Case-Control Studies
  • Cohort Studies
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • CpG Islands / genetics
  • DNA Methylation
  • Endometrial Neoplasms / genetics*
  • Endometrial Neoplasms / metabolism
  • Endometrial Neoplasms / pathology
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing*
  • Genetic Predisposition to Disease*
  • Genotype
  • Humans
  • Middle Aged
  • MutL Protein Homolog 1
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic


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