CpG Island Methylation in Gastroenterologic Neoplasia_文档之家

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当前位置：文档之家 > CpG Island Methylation in Gastroenterologic Neoplasia CpG Island Methylation in Gastroenterologic Neoplasia CpG Island Methylation in Gastroenterologic Neoplasia:A Maturing FieldASIF RASHID*and JEAN PIERRE J.ISSA?*Department of Pathology and?Department of Leukemia,The University of Texas M.D.Anderson Cancer Center,Houston,TexasFifteen years after the?rst demonstration of epigenetic tumor-suppressor gene inactivation associated with pro-moter methylation,the?eld has reached a level of understanding that threatens a rewriting of established biologic concepts.In gastrointestinal malignancies,epi-genetic analysis has led to novel hypotheses regarding the etiology of age-associated cancer susceptibility and the interactions between environmental exposures and neoplasia.Methylation pro?ling has uncovered a distinct pathway to colorectal neoplasia that may arise from a hitherto underestimated precursor lesion,the proximal hyperplastic polyp-serrated adenoma pathway.Epige-netic information has shown promise in clarifying sus-ceptibility to cancer and de?ning poor prognosis groups in gastrointestinal cancers.Finally,the?eld has engen-dered renewed interest in therapeutic targeting of epi-genetic regulatory molecules,and several such drugs are currently in clinical trials.It is likely that epigenetic pathways will be integrated in the routine management of gastrointestinal malignancies over the next decade. M ethylation of cytosine is the only known physio-logic modi?cation of DNA in human cells,andmethylated cytosine has been referred to as the elusive?fth base.1The evolutionary raison d’être of DNA meth-ylation has not been fully elucidated,but a currentleading hypothesis is that it evolved to silence and sup-press the harmful effects of parasitic sequences in com-plex genomes such as retroviruses and interspersed re-peats.2In normal human cells,DNA methylation is nowregarded as an important mechanism of epigenetic reg-ulation,i.e.,stable change in gene expression that is notrelated to changes in the primary structure of DNA.1This epigenetic effect is particularly striking when DNAmethylation affects promoter CpG islands.3CpG islandsare0.5–2kilobase regions rich in the cytosine-guaninedinucleotides and are present in the5=region of abouthalf of all human genes.Methylation of cytosines withinCpG islands is associated with loss of protein expressionby repression of transcription and is observed in physi-ologic conditions such as X-chromosome inactivationand imprinting.1,3DNA Methylation in CancerDNA methylation changes in paradoxical direc-tions in neoplastic cells.4Global decreases in5-methyl-cytosine content(hypomethylation)have been associated with tumorigenesis,5including colon cancer.6These de-creases have been proposed to lead to genetic instability,7 and mouse models show tissue-speci?c increased tumor formation associated with profound hypomethylation.8,9 It is not clear whether this degree of hypomethylation is relevant to human tumorigenesis,where decreases of 10%–20%are the norm.10Another molecular defect commonly present in neoplasia is de novo CpG island methylation.Methylation of cytosine at CpG sequences is associated with silencing of tumor suppressor genes in cancer11and is an alternative mechanism to gene muta-tions and allelic losses,as demonstrated for a variety of loci,including VHL,12MLH1,13and P16.14Methylation in cancer shows signi?cant tissue speci?city.For exam-ple,MLH1is methylated in colorectal13and gastric15 carcinomas but is infrequently methylated in esophage-al16and hepatocellular carcinomas.17Similarly,VHL is almost exclusively methylated in renal cancers.12This is presumed to be related to a tissue-speci?c selective ad-vantage imparted by the methylation events but could also be related to tissue-speci?c exposures.17At this point,the causes of hypomethylation or hypermethyl-ation in cancer are not known,and the relationship between these two contradictory events also remains obscure.Aging and MethylationIn the colon,studies of methylation in cancer unexpectedly revealed a hitherto unknown aspect of DNA aging.Careful quantitative studies showed that many genes highly methylated in cancer also have a low but measurable degree of methylation in apparently nor-Abbreviation used in this paper:CIMP,CpG island methylator phenotype.?2004by the American Gastroenterological Association0016-5085/04/$30.00doi:10.1053/j.gastro.2004.09.007GASTROENTEROLOGY2004;127:1578–1588上一页下一页