ArticleProceedings of the National Academy of Sciences of the United States of America1999
Mechanisms of inactivation of mismatch repair genes in human colorectal cancer cell lines: the predominant role of hMLH1.
Article in Proceedings of the National Academy of Sciences of the United States of America, 1999. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 120 citations in OpenAlex.
- Trial
- Article
- Immunoexpression of TS, p53, COX2, EGFR, MSH6 and MLH1 biomarkers and its correlation with degree of differentiation, tumor staging and prognostic factors in colorectal adenocarcinoma: a retrospective longitudinal study.Sao Paulo medical journal = Revista paulista de medicina · 2019Observational
- The Role of Abnormal Methylation of Wnt5a Gene Promoter Regions in Human Epithelial Ovarian Cancer: A Clinical and Experimental Study.Analytical cellular pathology (Amsterdam) · 2018Article
- Small molecule inhibitors uncover synthetic genetic interactions of human flap endonuclease 1 (FEN1) with DNA damage response genes.PloS one · 2017Article
- The Role of Stem Cell DNA Methylation in Colorectal Carcinogenesis.Stem cell reviews and reports · 2016Review
- Article
- S-phase-specific radiosensitization by gemcitabine for therapeutic carbon ion exposure in vitro.Journal of radiation research · 2016Article
- Pharmacogenetics research on chemotherapy resistance in colorectal cancer over the last 20 years.World journal of gastroenterology · 2014Review
- DNA methyltransferases, DNA damage repair, and cancer.Advances in experimental medicine and biology · 2013Review
- Microsatellite instability in metastatic colorectal cancer: a review of pathology, response to chemotherapy and clinical outcome.Medical oncology (Northwood, London, England) · 2012Review
- Epigenomic analysis of aberrantly methylated genes in colorectal cancer identifies genes commonly affected by epigenetic alterations.Annals of surgical oncology · 2011Article
- Article
- Involvement of promoter methylation in the regulation of Pregnane X receptor in colon cancer cells.BMC cancer · 2011Article
- Modulation of mismatch repair and genomic stability by miR-155.Proceedings of the National Academy of Sciences of the United States of America · 2010Article
- Cell growth, global phosphotyrosine elevation, and c-Met phosphorylation through Src family kinases in colorectal cancer cells.Proceedings of the National Academy of Sciences of the United States of America · 2008Article
- No evidence for dual role of loss of heterozygosity in hereditary non-polyposis colorectal cancer.Oncogene · 2007Article
- Article
- Epigenetic silencing of AXIN2 in colorectal carcinoma with microsatellite instability.Oncogene · 2006Article
- Gene expression signatures for colorectal cancer microsatellite status and HNPCC.British journal of cancer · 2005Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Fifteen to twenty-five percent of sporadic colorectal carcinomas are replication error (RER) positive. Because the frequency of mutations in the mismatch repair genes (hMLH1 and hMSH2) is low in these tumors, we have investigated the role of mutational inactivation, methylation of the promoter region, and loss of heterozygosity (LOH) as a possible explanation for the mutator phenotype of RER+ colorectal cancer cell lines. Genomic DNA was extracted from a panel of 49 human colorectal cancer cell lines. The RER status was determined by amplification of BAT-26. All exons of hMLH1 and hMSH2 were amplified with the PCR and screened by using single-strand conformational polymorphism and direct sequencing. The methylation status was ascertained by methylation-specific PCR after bisulfite modification of DNA. Western blotting for hMLH1 was performed on methylated cell lines before and after the addition of the demethylating agent 5-azacytidine. LOH was sought by GENESCAN analysis of amplified CA repeat markers and indirectly by determining the number of homozygotes in the cell lines and human random controls. Twelve cell lines from ten tumors (24%) were RER+. Hypermethylation of the hMLH1 promoter occurred in five of ten (50%) RER+ tumors, whereas three of thirty-two (6%) RER tumors showed partial methylation. None of the fully methylated cell lines expressed hMLH1, although all reexpressed hMLH1 after treatment with 5-azacytidine. There was no LOH in the RER+ tumors in either hMLH1 or hMSH2. Our results suggest that mutations of hMLH1 together with hypermethylation of the promoter region, but not LOH, are the cause of the mutator phenotype in the majority (70%) of RER+ tumors.
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