Alterations in DNA Methylation: A Fundamental Aspect of Neoplasia

Baylin, Stephen B.; Herman, James G.; Graff, Jeremy R.; Vertino, Paula M.; Issa, Jean Pierre J.

doi:10.1016/s0065-230x(08)60702-2

Cited by 1,703 publications

(1,163 citation statements)

References 181 publications

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“…On the other hand, methylated DNA could be recognized by speci®c DNA binding proteins as MeCP2, which binds DNA with a single CpG methylation and have been demonstrated to inhibit transcription (Meehan et al, 1992;Nan et al, 1997). Thus, the e ect of methylation of the 3'-UTR (a region without CpG islands) on transcription should be di erent to that of methylation of promoter regions, where multiple CpG sites of the CpG islands are involved and the density of methylation in¯uences the level of transcription (Baylin et al, 1998). In fact, as observed in Figure 8, methylation of only two of the CpG sites (those recognized by the XhoI and HpaII restriction enzymes) is su cient to interfere with transcription.…”

Section: Discussionmentioning

confidence: 99%

Hypermethylation of the cell cycle inhibitor p15INK4b 3′-untranslated region interferes with its transcriptional regulation in primary lymphomas

et al. 1999

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Section: Discussionmentioning

confidence: 99%

Hypermethylation of the cell cycle inhibitor p15INK4b 3′-untranslated region interferes with its transcriptional regulation in primary lymphomas

et al. 1999

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“…13 The recently described CpG island methylator phenotype is an alternative tumorigenesis pathway characterized by methylation of multiple promoter regions of tumor suppressor genes harboring CpG islands. Recent studies have shown that CpG island methylator phenotype is very common in sporadic serrated adenomas, and especially in the hyperplastic polyps of hyperplastic polyposis.…”

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confidence: 99%

Progressive methylation during the serrated neoplasia pathway of the colorectum

et al. 2005

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Serrated adenoma is a recently described entity characterized by having combined architectural features of hyperplastic polyps and classical adenoma. To understand the role of gene regulation in the progression of the serrated neoplasia pathway, we examined the methylation profiles of the promoter regions of 19 genes, DNA ploidy, and mutator phenotype status. In all, 40 sporadic, classical serrated adenomas were pathologically reviewed and divided into four pathologic groups according to their histologic grades. Methylation-specific PCR was performed using primers for p16, hMLH1, RASSF1A, APC, HIC-1, DAPK, MGMT, SLC5A8, RB1, HCadherin, E-Cadherin, TIMP3, PTEN, THBS1, LKB1, p14, p15, FHIT, and VHL. Dual flow-cytometric analyses using cytokeratin and DAPI and MSI studies using BAT26 were also performed. Methylation was observed in 2.5-82.5% (mean 33.9%) of the CpG islands in the promoter regions of 16 genes. The tumors with higher histologic grades, including carcinomas, showed more extensive methylation compared to those with lower grades, and serrated adenomas in the right colon showed more frequent methylation than those in the left (Po0.05). Tumor-specific promoter methylation of SLC5A8 was observed in 33 (82.5%) of the serrated adenomas. Aneuploidization with near-diploid DNA indices was detected in four out of 28 cases examined (14.3%); two were low-grade serrated adenomas and two were carcinomas in the left colon. The high mutator phenotype was not observed in any of the cases examined. Our results indicate that: (1) aberrant, widespread methylation of CpG islands increases with the histological progression of serrated adenomas; (2) methylation of SLC5A8 is an early event; and (3) additional methylation of the p16, p14, MGMT, TIMP3, and FHIT genes are important tumorigenic steps in the serrated neoplasia pathway.

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“…This is a rather outdated view of cancer aetiology which does not take into account a large amount of heavy arguments against it, as well as an extraordinary number of new acquisitions. Genomic instability, 39 microsatellite instability, 40 and defects of the DNA mismatch repair system, 41 as well as alterations of DNA methylation [42][43][44][45][46] and hystone acethylation/ deacethylation, [47][48][49][50][51][52] not only have been found to be involved in the genesis of cancer, but also and more importantly, have largely contributed to the view of cancer as an epigenetic 53,54 rather than a genetic disease. 55 As more recently reported, 56 cancer appears to begin with epigenetic alterations in stem cells, thus implying that epigenetic (or non mutational) loss of gene expression comes more commonly before any mutations in cancer.…”

Section: Discussionmentioning

confidence: 99%

Retinoblastoma epidemiology: Does the evidence matter?

Milardi

Francesco

Leonardo³

et al. 2007

European Journal of Cancer

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AneuploidyTwo hit theory Microsatellite instabilityChromosome instability Epigenetic A B S T R A C T It has been proposed that retinoblastoma is 'caused' by two sequential mutations affecting the RB1 gene, but this is a rather outdated view of cancer aetiology that does not take into account a large amount of new acquisitions such as chromosomal and epigenetic alterations.Retinoblastoma remains probably the only cancer in which the rather simplistic 'two hit' mutational model is still considered of value, although cancer is known to be associated with genomic and microsatellite instability, defects of the DNA mismatch repair system, alterations of DNA methylation and hystone acethylation/deacethylation, and aneuploidy.Moreover, as it is shown herein, the predictions made by the 'two hit' model, are not fulfilled by the clinical and epidemiological data reported so far. Moreover, while the role of mutational events in cancer has been largely questioned in the more recent literature, no serious effort has been done to investigate the role of epigenetic alterations and aneuploidy in retinoblastoma.Through the analysis of the specialised literature and a set of original epidemiological and biological data concerning retinoblastoma, the authors illustrate the evidences arguing against the 'two hit' hypothesis and propose that epigenetic factors and aneuploidy play central roles in the disease.

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Alterations in DNA Methylation: A Fundamental Aspect of Neoplasia

Cited by 1,703 publications

References 181 publications

Hypermethylation of the cell cycle inhibitor p15INK4b 3′-untranslated region interferes with its transcriptional regulation in primary lymphomas

Hypermethylation of the cell cycle inhibitor p15INK4b 3′-untranslated region interferes with its transcriptional regulation in primary lymphomas

Progressive methylation during the serrated neoplasia pathway of the colorectum

Retinoblastoma epidemiology: Does the evidence matter?

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