Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma
James G. Herman,Asad Umar,Kornelia Polyak,Jeremy R. Graff,Nita Ahuja,Jean Pierre J. Issa,Sanford Markowitz,Sanford Markowitz,James K V Willson,Stanley R. Hamilton,Kenneth W. Kinzler,Michael F. Kane,Richard D. Kolodner,Bert Vogelstein,Thomas A. Kunkel,Stephen B. Baylin +15 more
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The results suggest that microsatellite instability in sporadic colorectal cancer often results from epigenetic inactivation of hMLH1 in association with DNA methylation.Abstract:
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.read more
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PD-1 Blockade in Tumors with Mismatch-Repair Deficiency
Dung T. Le,Jennifer N. Uram,Hao Wang,Bjarne Bartlett,Holly Kemberling,Aleksandra Eyring,Andrew D. Skora,Brandon Luber,Nilofer S. Azad,Daniel A. Laheru,Barbara A. Biedrzycki,Ross C. Donehower,Atif Zaheer,George A. Fisher,Todd S. Crocenzi,James J. Lee,Steven M. Duffy,Richard M. Goldberg,Richard M. Goldberg,Albert de la Chapelle,Albert de la Chapelle,Minori Koshiji,Feriyl Bhaijee,Thomas Huebner,Ralph H. Hruban,Laura D. Wood,Nathan Cuka,Drew M. Pardoll,Nickolas Papadopoulos,Kenneth W. Kinzler,Shibin Zhou,Toby C. Cornish,Janis M. Taube,Robert A. Anders,James R. Eshleman,Bert Vogelstein,Luis A. Diaz +36 more
TL;DR: This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab, and high somatic mutation loads were associated with prolonged progression-free survival.
Journal ArticleDOI
The fundamental role of epigenetic events in cancer
Peter A. Jones,Stephen B. Baylin +1 more
TL;DR: This review discusses patterns of DNA methylation and chromatin structure in neoplasia and the molecular alterations that might cause them and/or underlie altered gene expression in cancer.
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Gene Silencing in Cancer in Association with Promoter Hypermethylation
TL;DR: The mechanisms of gene silencing in cancer and clinical applications of this phenomenon are reviewed, especially tumor-suppressor genes.
Journal ArticleDOI
CpG island methylator phenotype in colorectal cancer.
Minoru Toyota,Nita Ahuja,Mutsumi Ohe-Toyota,James G. Herman,Stephen B. Baylin,Jean Pierre J. Issa +5 more
TL;DR: A pathway in colorectal cancer appears to be responsible for the majority of sporadic tumors with mismatch repair deficiency, and is defined as CpG island methylator phenotype (CIMP); CIMP+ tumors also have a high incidence of p16 and THBS1 methylation, and they include the majority with microsatellite instability related to hMLH 1 methylation.
Journal ArticleDOI
Cancer-epigenetics comes of age
Peter A. Jones,Peter W. Laird +1 more
TL;DR: Current mechanistic understanding of the role of DNA methylation in malignant transformation is reviewed, and it is suggested Knudson's two–hit hypothesis should be expanded to include epigenetic mechanisms of gene inactivation.
References
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Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands
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Journal ArticleDOI
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Journal ArticleDOI
Inactivation of the Type II TGF-β Receptor in Colon Cancer Cells with Microsatellite Instability
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.
Journal ArticleDOI
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.