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cpg island methylator phenotype in adenocarcinomas from the digestive tract:Methods,conclusions,and controversies

World Journal of Gastrointestinal Oncology 2017年第3期9卷 105-120页

作者： Francisco Sánchez-Vega Valer Gotea Yun-Ching Chen Laura Elnitski Genomic Functional Analysis Section National Human Genome Research InstituteNational Institutes of HealthRockvilleMD 20852United States

Over the last two decades, cancer-related alterations in DNA methylation that regulate transcription have been reported for a variety of tumors of the gastrointestinal tract. Due to its relevance for translational research, great emphasis has been placed on the analysis and molecular characterization of the cpg island methylator phenotype(CIMP), defined as widespread hypermethylation of cpg islands in clinically distinct subsets of cancer patients. Here, we present an overview of previous work in this field and also explore some open questions using crossplatform data for esophageal, gastric, and colorectal adenocarcinomas from The Cancer Genome Atlas. We provide a data-driven, pan-gastrointestinal stratification of individual samples based on CIMP status and we investigate correlations with oncogenic alterations, including somatic mutations and epigenetic silencing of tumor suppressor genes. Besides known events in CIMP such as BRAF V600 E mutation, CDKN2 A silencing or MLH1 inactivation, we discuss the potential role of emerging actors such as Wnt pathway deregulation through truncating mutations in RNF43 and epigenetic silencing of WIF1. Our results highlight the existence of molecular similarities that are superimposed over a larger backbone of tissue-specific features and can be exploited to reduce heterogeneity of response in clinical trials.

关键词： cpg island methylator phenotype cpg island Promoter DNA methylation Hypermethylation Gastrointestinal cancer

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DNA Methylomes in cpg island methylator phenotype(CIMP) Colon Cancer:new screening marks proposal

DNA Methylomes in CpG Island Methylator Phenotype(CIMP) Colo...

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第十二次全国医学遗传学学术会议

作者： Hongli Yan Guan’nan Tang Yiliang Zhang Yuzhao Wang Shuhan SUN Department of medical genetics Second Military Medical University

Background & Aims:DNA methylation is essential for normal development and is frequently altered in *** island methylator phenotype(CIMP) is a subset of colorectal cancers was postulated to have a higher propensity for DNA ***,the validity of CIMP,its molecular basis,and its prognostic values are highly *** aims of this study were to(1) compare and characterize the unique features of DNA methylomes of CIMP with Non-CIMP colonrectal cancers;(2) propose a new panel of valuable markers for CIMP screening. Methods & Results:Here we utilized MBD-isolated Genome Sequencing(MiGS) to map the DNA methylomes of three sets of normal colon,non-CIMP colon cancers,and CIMP colon *** regions only robust hypermethylated in CIMP tumors were evaluated in 120 colorectal tumors by Bisulfite genomic sequencing or Methylation Specific PCR(MSP).We found 4,800 sites were hypermethylated in both non-CIMP and CIMP colon cancers when compared with normal *** those sites,318 sites were robust hypermethylated in CIMP tumors only. Methylation of these cpg islands regulates 122 key genes in tumorgenesis and progress.A panel of 5 new markers was proposed for CIMP screening in 120 consecutive colon samples,13.3% (16/120) were methylated in all 5 markers and 87.5%(14/16) were *** the markers described by Weisenberger et al.,22.5%(27/120) were methylated in all 5 markers and only 51.8%(14/27) were MSI ***:CIMP are a subset of colorectal cancer has unique features in DNA *** genes only hypermethylated in CIMP tumors shed lights on exploration the mechanism of CIMP tumorgenesis and provide new targets for cancer therapies. The new panel of markers facilitates CIMP screening in sporadic colorectal cancers.

关键词： Colorectal cancer cpg island methylator phenotype MBD-isolated Genome Sequencing DNA methylome

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Multiple primary colorectal cancer: Individual or familial predisposition?

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World Journal of Gastrointestinal Oncology 2015年第12期7卷 434-444页

作者： José A Pajares José Perea Department of Gastreoenterology Gregorio Maranon University Hospital Department of Surgery 12 de Octubre University Hospital

Colorectal carcinoma(CRC) is one of the most frequent cancers. Along the surface of the large bowel, several foci of CRC may appear simultaneously or over the time. The development of at least two different tumours has been defined as multiple primary CRC(MPCRC):When more than one tumour is diagnosed at the same time, it is known as synchronous CRC(SCRC), while when a second neoplasm is diagnosed some time after the resection and/or diagnosis of the first lesion, it is called metachronous CRC(MCRC). Multiple issues can promote the development of MPCRC, ranging from different personal factors, such as environmental exposure, to familial predisposition due to hereditary factors. However, most studies do not distinguish this dichotomy. High- and low-pentrance genetic variants are involved in MPCRC. An increased risk for MPCRC has been described in Lynch syndrome, familial adenomatous polyposis, and serrated polyposis. Non-syndromic familial CRCs should also be considered as risk factors for MPCRC. Environmental factors can promote damage to colon mucosae that enable the concurrence of MPCRC. Epigenetics are thought to play a major role in the carcinogenesis of sporadic MPCRC. The methylation state of the DNA depends on multiple environmental factors(e.g., smoking and eating foods cooked at high temperatures), and this can contribute to increasing the MPCRC rate. Certain clinical features may also suggest individual predisposition for MPCRC. Different etiopathogenic factors are suspected to be involved in SCRC and MCRC, and different familial vs individual factors may be implicated. MCRC seems to follow a familial pattern, whereas individual factors are more important in SCRC. Further studies must be carried out to know the molecular basis of risks for MPCRC in order to modify, if necessary, its clinical management, especially from a preventive point of view.

关键词： Multiple primary colorectal cancer Synchronous colorectal cancer Metachronous colorectal cancer Chromosomal instability Microsatellite instability cpg island methylator phenotype

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