TY - JOUR
T1 - Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma
AU - Herman, James G.
AU - Umar, Asad
AU - Polyak, Kornelia
AU - Graff, Jeremy R.
AU - Ahuja, Nita
AU - Issa, Jean Pierre J.
AU - Markowitz, Sanford
AU - Willson, James K.V.
AU - Hamilton, Stanley R.
AU - Kinzler, Kenneth W.
AU - Kane, Michael F.
AU - Kolodner, Richard D.
AU - Vogelstein, Bert
AU - Kunkel, Thomas A.
AU - Baylin, Stephen B.
PY - 1998/6/9
Y1 - 1998/6/9
N2 - Inactivation of the genes involved in DNA mismatch repair is associated with microsatellite instability (MSI) in colorectal cancer. We report that hypermethylation of the 5' CpG island of hMLH1 is found in the majority of sporadic primary colorectal cancers with MSI, and that this methylation was often, but not invariably, associated with loss of hMLH1 protein expression. Such methylation also occurred, but was less common, in MSI- tumors, as well as in MSI+ tumors with known mutations of a mismatch repair gene (MMR). No hypermethylation of hMSH2 was found. Hypermethylation of colorectal cancer cell lines with MSI also was frequently observed, and in such cases, reversal of the methylation with 5-aza-2'-deoxycytidine not only resulted in reexpression of hMLH1 protein, but also in restoration of the MMR capacity in MMR-deficient cell lines. Our results suggest that microsatellite instability in sporadic colorectal cancer often results from epigenetic inactivation of hMLH1 in association with DNA methylation.
AB - Inactivation of the genes involved in DNA mismatch repair is associated with microsatellite instability (MSI) in colorectal cancer. We report that hypermethylation of the 5' CpG island of hMLH1 is found in the majority of sporadic primary colorectal cancers with MSI, and that this methylation was often, but not invariably, associated with loss of hMLH1 protein expression. Such methylation also occurred, but was less common, in MSI- tumors, as well as in MSI+ tumors with known mutations of a mismatch repair gene (MMR). No hypermethylation of hMSH2 was found. Hypermethylation of colorectal cancer cell lines with MSI also was frequently observed, and in such cases, reversal of the methylation with 5-aza-2'-deoxycytidine not only resulted in reexpression of hMLH1 protein, but also in restoration of the MMR capacity in MMR-deficient cell lines. Our results suggest that microsatellite instability in sporadic colorectal cancer often results from epigenetic inactivation of hMLH1 in association with DNA methylation.
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U2 - 10.1073/pnas.95.12.6870
DO - 10.1073/pnas.95.12.6870
M3 - Article
C2 - 9618505
AN - SCOPUS:13144266670
SN - 0027-8424
VL - 95
SP - 6870
EP - 6875
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 12
ER -