Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers
Martina L. Veigl,Lakshmi Kasturi,Joseph Olechnowicz,Aihong Ma,James Lutterbaugh,Sumudra Periyasamy,Guo Min Li,James T. Drummond,Paul Modrich,W. David Sedwick,Sanford D. Markowitz +10 more
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In this article, the absence of hMLH1 protein was associated with the methylation of the HMLH 1 gene promoter, which is intimately associated with this epigenetic silencing mechanism.Abstract:
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. Previ- ously 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 expres- sion 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 methyl- ation is intimately associated with this epigenetic silencing mechanism.read more
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Sanford D. Markowitz,Jing Wang,Lois Myeroff,Ramon Parsons,Lu Zhe Sun,James Lutterbaugh,Robert S. Fan,Elizabeth Zborowska,Kenneth W. Kinzler,Bert Vogelstein,Bert Vogelstein,Michael G. Brattain,James K V Willson +12 more
TL;DR: Human colon cancer cell lines with high rates of microsatellite instability were found to harbor mutations in the type II TGF-beta receptor (RII) gene, which links DNA repair defects with a specific pathway of tumor progression.
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Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer
Fredrick S. Leach,Nicholas C. Nicolaides,Nickolas Papadopoulos,Bo Liu,Jin Jen,Ramon Parsons,Päivi Peltomäki,Pertti Sistonen,Lauri A. Aaltonen,Minna Nyström-Lahti,Xin Yuan Guan,Ji Zhang,Paul S. Meltzer,Jing Wei Yu,Fa Ten Kao,David J. Chen,Karen M. Cerosaletti,R. E. Keith Fournier,Sean Todd,Tracey B. Lewis,Robin J. Leach,Susan L. Naylor,Jean Weissenbach,Jukka-Pekka Mecklin,Heikki Järvinen,Gloria M. Petersen,Stanley R. Hamilton,Jane Green,Jeremy R. Jass,Patrice Watson,Henry T. Lynch,Jeffrey M. Trent,Albert de la Chapelle,Kenneth W. Kinzler,Bert Vogelstein +34 more
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5' CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers.
Adrian Merlo,James G. Herman,Li Mao,Daniel J. Lee,Edward Gabrielson,Peter C. Burger,Stephen B. Baylin,David Sidransky +7 more
TL;DR: De novo methylation of the 5′ CpG island of p16 was found in approximately 20% of different primary neoplasms, but not in normal tissues, potentially representing a common pathway of tumour suppressor gene inactivation in human cancers.