Germline and somatic mutation analyses in the DNA mismatch repair gene MLH3: Evidence for somatic mutation in colorectal cancers

Steven M. Lipkin, Victoria Wang, Dan L. Stoler, Garth R. Anderson, Ilan Kirsch, Don Hadley, Henry T. Lynch, Francis S. Collins

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

DNA mismatch repair is of considerable scientific and medical importance because of its essential role in maintaining genomic integrity, and its association with hereditary non-polyposis colon cancer (HNPCC). Germline mutations in five mismatch repair genes (MLH1, MSH2, PMS1, PMS2, and MSH6) have been associated with HNPCC susceptibility. Our laboratory recently identified MLH3, a novel DNA mismatch repair gene. We screened the MLH3 coding sequence in 60 probands with increased genetic risk factors for colorectal cancer susceptibility and no mutations in the other candidate genes. No definite MLH3 germline mutations were found. We subsequently screened 36 colon tumors, and discovered an appreciable frequency of somatic MLH3 coding mutations in MSI-H tumors (25%). In four of six tumors, evidence of biallelic inactivation was noted. Furthermore, MLH3 nonsense mutations were identified in two of 12 microsatellite stable (MSS) tumors with 14q24 loss of heterozygosity. While our analyses do not exclude the existence of germline MLH3 mutations in patients with increased genetic risk factors for colorectal cancer susceptibility, they suggest such mutations are uncommon in this patient population. The finding of an appreciable frequency of somatic MLH3 mutations is consistent with a possible role for this gene in the progression of colorectal cancer tumorigenesis. Published 2001 Wiley-Liss, Inc.

Original languageEnglish
Pages (from-to)389-396
Number of pages8
JournalHuman Mutation
Volume17
Issue number5
DOIs
StatePublished - 2001
Externally publishedYes

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DNA Mismatch Repair
Germ-Line Mutation
Colorectal Neoplasms
Mutation
Colonic Neoplasms
Genes
Neoplasms
Nonsense Codon
Loss of Heterozygosity
Microsatellite Repeats
Colon
Carcinogenesis
Population

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Lipkin, S. M., Wang, V., Stoler, D. L., Anderson, G. R., Kirsch, I., Hadley, D., ... Collins, F. S. (2001). Germline and somatic mutation analyses in the DNA mismatch repair gene MLH3: Evidence for somatic mutation in colorectal cancers. Human Mutation, 17(5), 389-396. https://doi.org/10.1002/humu.1114

Germline and somatic mutation analyses in the DNA mismatch repair gene MLH3 : Evidence for somatic mutation in colorectal cancers. / Lipkin, Steven M.; Wang, Victoria; Stoler, Dan L.; Anderson, Garth R.; Kirsch, Ilan; Hadley, Don; Lynch, Henry T.; Collins, Francis S.

In: Human Mutation, Vol. 17, No. 5, 2001, p. 389-396.

Research output: Contribution to journalArticle

Lipkin, Steven M. ; Wang, Victoria ; Stoler, Dan L. ; Anderson, Garth R. ; Kirsch, Ilan ; Hadley, Don ; Lynch, Henry T. ; Collins, Francis S. / Germline and somatic mutation analyses in the DNA mismatch repair gene MLH3 : Evidence for somatic mutation in colorectal cancers. In: Human Mutation. 2001 ; Vol. 17, No. 5. pp. 389-396.
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