Aberrant DNA methylation in hereditary nonpolyposis colorectal cancer without mismatch repair deficiency

Gastroenterology. 2010 May;138(5):1854-62. doi: 10.1053/j.gastro.2010.01.035. Epub 2010 Jan 25.


Background & aims: Approximately half of the families that fulfill Amsterdam criteria for Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) do not have evidence of the germline mismatch repair gene mutations that define this syndrome and result in microsatellite instability (MSI). The carcinogenic pathways and the best diagnostic approaches to detect microsatellite stable (MSS) HNPCC tumors are unclear. We investigated the contribution of epigenetic alterations to the development of MSS HNPCC tumors.

Methods: Colorectal cancers were divided into 4 groups: (1) microsatellite stable, Amsterdam-positive (MSS HNPCC) (N = 22); (2) Lynch syndrome cancers (identified mismatch repair mutations) (N = 21); (3) sporadic MSS (N = 92); and (4) sporadic MSI (N = 46). Methylation status was evaluated for CACNAG1, SOCS1, RUNX3, NEUROG1, MLH1, and long interspersed nucleotide element-1 (LINE-1). KRAS and BRAF mutation status was analyzed.

Results: MSS HNPCC tumors displayed a significantly lower degree of LINE-1 methylation, a marker for global methylation, than any other group. Although most MSS HNPCC tumors had some degree of CpG island methylation, none presented a high index of methylation. MSS HNPCC tumors had KRAS mutations exclusively in codon 12, but none harbored V600E BRAF mutations.

Conclusions: Tumors from Amsterdam-positive patients without mismatch repair deficiency (MSS HNPCC) have certain molecular features, including global hypomethylation, that distinguish them from all other colorectal cancers. These characteristics could have an important impact on tumor behavior or treatment response. Studies are underway to further assess the cause and effects of these features.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adult
  • Aged
  • Aged, 80 and over
  • Base Sequence
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • Core Binding Factor Alpha 3 Subunit / genetics
  • DNA Methylation*
  • DNA Mismatch Repair*
  • Epigenesis, Genetic*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Genetic Predisposition to Disease
  • Genomic Instability
  • Humans
  • Long Interspersed Nucleotide Elements
  • Male
  • Microsatellite Repeats*
  • Middle Aged
  • Molecular Sequence Data
  • MutL Protein Homolog 1
  • Mutation*
  • Nerve Tissue Proteins / genetics
  • Nuclear Proteins / genetics
  • Pedigree
  • Phenotype
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins p21(ras)
  • Spain
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins / genetics
  • United States
  • ras Proteins / genetics


  • Adaptor Proteins, Signal Transducing
  • Basic Helix-Loop-Helix Transcription Factors
  • Core Binding Factor Alpha 3 Subunit
  • KRAS protein, human
  • MLH1 protein, human
  • NEUROG1 protein, human
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Runx3 protein, human
  • SOCS1 protein, human
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • MutL Protein Homolog 1
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins