Germline epimutation of MLH1 in individuals with multiple cancers

Nat Genet. 2004 May;36(5):497-501. doi: 10.1038/ng1342. Epub 2004 Apr 4.


Epigenetic silencing can mimic genetic mutation by abolishing expression of a gene. We hypothesized that an epimutation could occur in any gene as a germline event that predisposes to disease and looked for examples in tumor suppressor genes in individuals with cancer. Here we report two individuals with soma-wide, allele-specific and mosaic hypermethylation of the DNA mismatch repair gene MLH1. Both individuals lack evidence of genetic mutation in any mismatch repair gene but have had multiple primary tumors that show mismatch repair deficiency, and both meet clinical criteria for hereditary nonpolyposis colorectal cancer. The epimutation was also present in spermatozoa of one of the individuals, indicating a germline defect and the potential for transmission to offspring. Germline epimutation provides a mechanism for phenocopying of genetic disease. The mosaicism and nonmendelian inheritance that are characteristic of epigenetic states could produce patterns of disease risk that resemble those of polygenic or complex traits.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Age of Onset
  • Aged
  • Aged, 80 and over
  • Base Sequence
  • Breast Neoplasms / genetics
  • Carrier Proteins
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics
  • DNA Methylation*
  • DNA Repair
  • DNA, Neoplasm
  • DNA-Binding Proteins / genetics
  • Endometrial Neoplasms / genetics
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Germ-Line Mutation*
  • Humans
  • Loss of Heterozygosity
  • Male
  • Melanoma / genetics
  • Microsatellite Repeats
  • Middle Aged
  • Molecular Sequence Data
  • Mosaicism
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein
  • Neoplasm Proteins / genetics*
  • Neoplasms, Multiple Primary / genetics*
  • Nuclear Proteins
  • Proto-Oncogene Proteins / genetics
  • Skin Neoplasms / genetics
  • Spermatozoa / pathology


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • DNA, Neoplasm
  • DNA-Binding Proteins
  • MLH1 protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • MSH2 protein, human
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein