The role of MYH and microsatellite instability in the development of sporadic colorectal cancer

Br J Cancer. 2006 Nov 6;95(9):1239-43. doi: 10.1038/sj.bjc.6603421. Epub 2006 Oct 10.


Biallelic germline mutations in MYH are associated with colorectal neoplasms, which develop through a pathway involving somatic inactivation of APC. In this study, we investigated the incidence of the common MYH mutations in an Australian cohort of sporadic colorectal cancers, the clinicopathological features of MYH cancers, and determined whether inactivation of mismatch repair and base excision repair (BER) were mutually exclusive. The MYH gene was sequenced from lymphocyte DNA of 872 colorectal cancer patients and 478 controls. Two compound heterozygotes were identified in the cancer population and all three cancers from these individuals displayed a prominent infiltration of intraepithelial lymphocytes. In total, 11 heterozygotes were found in the cancer group and five in the control group. One tumour from an individual with biallelic germline mutation of MYH also demonstrated microsatellite instability (MSI) as a result of biallelic hypermethylation of the MLH1 promoter. Although MYH-associated cancers are rare in a sporadic colorectal population, this study shows that these tumours can develop through either a chromosomal or MSI pathway. Tumours arising in the setting of BER or mismatch repair deficiency may share a biological characteristic, which promotes lymphocytic infiltration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adult
  • Aged
  • Aged, 80 and over
  • Australia
  • Base Sequence
  • Carrier Proteins / genetics
  • Cohort Studies
  • Colorectal Neoplasms / etiology
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • DNA Glycosylases / genetics*
  • DNA Glycosylases / metabolism
  • DNA Methylation
  • DNA Mutational Analysis
  • Female
  • Gene Frequency
  • Germ-Line Mutation / genetics
  • Heterozygote
  • Humans
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Lymphocytes, Tumor-Infiltrating / pathology
  • Male
  • Microsatellite Instability*
  • Middle Aged
  • MutL Protein Homolog 1
  • Nuclear Proteins / genetics
  • Pedigree
  • Polymorphism, Genetic / genetics
  • Promoter Regions, Genetic / genetics


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • MLH1 protein, human
  • Nuclear Proteins
  • DNA Glycosylases
  • mutY adenine glycosylase
  • MutL Protein Homolog 1