Patterns of DNA methylation and chromatin structure are profoundly altered in neoplasia and include genome-wide losses of, and regional gains in, DNA methylation. The recent explosion in our knowledge of how chromatin organization modulates gene transcription has further highlighted the importance of epigenetic mechanisms in the initiation and progression of human cancer. These epigenetic changes -- in particular, aberrant promoter hypermethylation that is associated with inappropriate gene silencing -- affect virtually every step in tumour progression. In this review, we discuss these epigenetic events and the molecular alterations that might cause them and/or underlie altered gene expression in cancer.

The fundamental role of epigenetic events in cancer

This article reviews the mechanisms of gene silencing in cancer and clinical applications of this phenomenon. The silencing of genes, especially tumor-suppressor genes, is a key event in the development of cancer. The silencing can be effected by a disabling mutation or by a shutting down of the promoter region, the site at which transcription of the gene begins.

Gene Silencing in Cancer in Association with Promoter Hypermethylation

Analysis of 13,023 genes in 11 breast and 11 colorectal cancers revealed that individual tumors accumulate an average of ˜90 mutant genes but that only a subset of these contribute to the neoplastic process. Using stringent criteria to delineate this subset, we identified 189 genes (average of 11 per tumor) that were mutated at significant frequency. The vast majority of these genes were not known to be genetically altered in tumors and are predicted to affect a wide range of cellular functions, including transcription, adhesion, and invasion. These data define the genetic landscape of two human cancer types, provide new targets for diagnostic and therapeutic intervention and monitoring.

/pdf/consensus-coding-sequences-of-human-breast-and-colorectal-15edxp2i8x.pdf

Consensus coding sequences of human breast and colorectal cancers

Gene transcription can be activated or inhibited by a reversible modification of the gene; this modification is termed an epigenetic change. This account of epigenetics in cancer reviews the mechan...

/pdf/epigenetics-in-cancer-4240m6az4l.pdf

Epigenetics in Cancer

DNA methylation is a crucial epigenetic modification of the genome that is involved in regulating many cellular processes. These include embryonic development, transcription, chromatin structure, X chromosome inactivation, genomic imprinting and chromosome stability. Consistent with these important roles, a growing number of human diseases have been found to be associated with aberrant DNA methylation. The study of these diseases has provided new and fundamental insights into the roles that DNA methylation and other epigenetic modifications have in development and normal cellular homeostasis.

/pdf/dna-methylation-and-human-disease-3351ezm3g8.pdf

Dna methylation and human disease

CpG islands frequently contain gene promoters or exons and are usually unmethylated in normal cells. Methylation of CpG islands is associated with delayed replication, condensed chromatin and inhibition of transcription initiation. The investigation of aberrant CpG-island methylation in human cancer has primarily taken a candidate gene approach, and has focused on less than 15 of the estimated 45,000 CpG islands in the genome. Here we report a global analysis of the methylation status of 1,184 unselected CpG islands in each of 98 primary human tumours using restriction landmark genomic scanning (RLGS). We estimate that an average of 600 CpG islands (range of 0 to 4,500) of the 45,000 in the genome were aberrantly methylated in the tumours, including early stage tumours. We identified patterns of CpG-island methylation that were shared within each tumour type, together with patterns and targets that displayed distinct tumour-type specificity. The expression of many of these genes was reactivated by experimental demethylation in cultured tumour cells. Thus, the methylation of particular subsets of CpG islands may have consequences for specific tumour types.

Aberrant CpG-island methylation has non-random and tumour-type-specific patterns.

Restriction Landmark Genomic Scanning (RLGS), a method for the two-dimensional display of end-labeled DNA restriction fragments, was utilized to identify genomic regions of CpG island methylation associated with Human Colon Cancer. An Average of 1.5% of the RLGS loci/spots are lost or significantly reduced in sporadic primary colon tumors relative to normal colon mucosa from the same patient. This may represent tumor specific methylation of about 400 CpG islands in sporadic colon cancer. A number of RLGS loci exhibiting frequent loss associated with colon cancer were cloned. DNA sequence analysis indicated that the RLGS loci identified genomic regions characteristic of CpG islands. A number of methods including bisulfite genomic sequencing as well as quantitative MassARRAY methylation analysis (www.sequenom.com) confirmed tumor specific methylation at several of these loci. DNA database searches indicated that candidate genes associated with these loci include transcription factors and genes involved in s...

Identification of DNA methylation in 3' genomic regions that are associated with upregulation of gene expression in colorectal cancer.

http://yadda.icm.edu.pl/yadda/element/bwmeta1.element.baztech-article-BAT1-0033-0012/c/httpwww_ein_org_plpodstronywydania42pdf01.pdf

Xueli Zhang

Papers

Aberrant CpG-island methylation has non-random and tumour-type-specific patterns.

Identification of DNA methylation in 3' genomic regions that are associated with upregulation of gene expression in colorectal cancer.

Reliability Based Optimal Preventive Maintenance Policy of Series-parallel systems

Artificial Intelligence-Assisted Analysis of Tumor Growth Pattern, Tumor-Infiltrating Lymphocytes, And Survival from Colorectal Cancer