MLH1 germline epimutations in selected patients with early-onset non-polyposis colorectal cancer

Clin Genet. 2007 Mar;71(3):232-7. doi: 10.1111/j.1399-0004.2007.00751.x.


Recently, the germline epigenetic inactivation of MLH1 has been reported in a number of patients with early-onset colorectal cancer among other characteristics. The aim of the present study is to evaluate the presence of MLH1 germline epimutations in selected colorectal cancer patients suspected of hereditary non-polyposis colorectal cancer (HNPCC) in order to determine in which patients the MLH1 epigenetic test should be performed. From a total of 109 microsatellite instability (MSI)-positive HNPCC-suspected patients, 11 showed a lack of MLH1 expression in tumor tissue and no germline mutations in the mismatch repair (MMR) genes. In nine of these cases and in three additional patients with multiple tumors, the study of the germline MLH1 promoter hypermethylation was performed by means of methylation-specific PCR and combined bisulfite-restriction analysis techniques. One of the selected patients resulted positive for the MLH1 epimutation, which was confirmed in the DNA extracted from buccal lavage. The patient with the epimutation had developed an epidermoid lip carcinoma and an early-onset colorectal tumor with MSI, no MLH1 expression, and loss of heterozygosity of the gene. Parents and siblings did not carry the epigenetic alteration, suggesting a de novo mechanism. Although germline MLH1 epimutations seem to be mostly uncommon, when the cases are well selected, the probability of finding them increases. Thus, taking into account ours and previous reports, we propose that screening for MLH1 epimutations in blood DNA could be performed in early-onset colorectal cancer patients with MSI, lack of MLH1 expression in the tumor, and no germline mutations in the MMR genes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Age of Onset
  • Base Sequence
  • Colorectal Neoplasms, Hereditary Nonpolyposis / diagnosis*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / epidemiology
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics
  • DNA Methylation
  • Genetic Testing
  • Germ-Line Mutation*
  • Humans
  • Microsatellite Instability
  • Molecular Sequence Data
  • MutL Protein Homolog 1
  • Nuclear Proteins / genetics*
  • Pedigree


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