Skip to main content
Journal cover image

Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers.

Publication ,  Journal Article
Veigl, ML; Kasturi, L; Olechnowicz, J; Ma, AH; Lutterbaugh, JD; Periyasamy, S; Li, GM; Drummond, J; Modrich, PL; Sedwick, WD; Markowitz, SD
Published in: Proc Natl Acad Sci U S A
July 21, 1998

Mutations of DNA mismatch repair genes, including the hMLH1 gene, have been linked to human colon and other cancers in which defective DNA repair is evidenced by the associated instability of DNA microsatellite sequences (MSI). Germ-line hMLH1 mutations are causally associated with inherited MSI colon cancer, and somatic mutations are causally associated with sporadic MSI colon cancer. Previously however, we demonstrated that in many sporadic MSI colon cancers hMLH1 and all other DNA mismatch repair genes are wild type. To investigate this class of tumors further, we examined a group of MSI cancer cell lines, most of which were documented as established from antecedent MSI-positive malignant tumors. In five of six such cases we found that hMLH1 protein was absent, even though hMLH1-coding sequences were wild type. In each such case, absence of hMLH1 protein was associated with the methylation of the hMLH1 gene promoter. Furthermore, in each case, treatment with the demethylating agent 5-azacytidine induced expression of the absent hMLH1 protein. Moreover, in single cell clones, hMLH1 expression could be turned on, off, and on again by 5-azacytidine exposure, washout, and reexposure. This epigenetic inactivation of hMLH1 additionally accounted for the silencing of both maternal and paternal tumor hMLH1 alleles, both of which could be reactivated by 5-azacytidine. In summary, substantial numbers of human MSI cancers appear to arise by hMLH1 silencing via an epigenetic mechanism that can inactivate both of the hMLH1 alleles. Promoter methylation is intimately associated with this epigenetic silencing mechanism.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

July 21, 1998

Volume

95

Issue

15

Start / End Page

8698 / 8702

Location

United States

Related Subject Headings

  • Promoter Regions, Genetic
  • Nuclear Proteins
  • Neoplasms
  • Neoplasm Proteins
  • MutL Protein Homolog 1
  • Microsatellite Repeats
  • Humans
  • DNA Primers
  • DNA Methylation
  • Carrier Proteins
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Veigl, M. L., Kasturi, L., Olechnowicz, J., Ma, A. H., Lutterbaugh, J. D., Periyasamy, S., … Markowitz, S. D. (1998). Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc Natl Acad Sci U S A, 95(15), 8698–8702. https://doi.org/10.1073/pnas.95.15.8698
Veigl, M. L., L. Kasturi, J. Olechnowicz, A. H. Ma, J. D. Lutterbaugh, S. Periyasamy, G. M. Li, et al. “Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers.Proc Natl Acad Sci U S A 95, no. 15 (July 21, 1998): 8698–8702. https://doi.org/10.1073/pnas.95.15.8698.
Veigl ML, Kasturi L, Olechnowicz J, Ma AH, Lutterbaugh JD, Periyasamy S, et al. Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8698–702.
Veigl, M. L., et al. “Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers.Proc Natl Acad Sci U S A, vol. 95, no. 15, July 1998, pp. 8698–702. Pubmed, doi:10.1073/pnas.95.15.8698.
Veigl ML, Kasturi L, Olechnowicz J, Ma AH, Lutterbaugh JD, Periyasamy S, Li GM, Drummond J, Modrich PL, Sedwick WD, Markowitz SD. Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8698–8702.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

July 21, 1998

Volume

95

Issue

15

Start / End Page

8698 / 8702

Location

United States

Related Subject Headings

  • Promoter Regions, Genetic
  • Nuclear Proteins
  • Neoplasms
  • Neoplasm Proteins
  • MutL Protein Homolog 1
  • Microsatellite Repeats
  • Humans
  • DNA Primers
  • DNA Methylation
  • Carrier Proteins