Epigenetics – an overview | ScienceDirect Topics

6.8.1 DNA Hypermethylation in Cancer

CpG hypermethylation in gene promoters is the best characterized epigenetic abnormality in human malignancies. A common paradigm in cancer epigenetics is hypermethylation of the CpG-rich promoter regions of tumor-suppressor genes, resulting in epigenetic silencing of these genes (14). Indeed, for some of the most important tumor suppressorssuch as the CDKN2A gene encoding the p16 cell cycle inhibitorpromoter hypermethylation can be the most common mechanism underlying their functional loss during tumor formation, with the corresponding genetic pathways for loss of function (deletion/mutation) being utilized less commonly (230). Hypermethylated promoter DNA is associated with virtually every type of human tumor, with each type of tumor having its own signature of methylated genes, such as the methylation of GSTP1 in prostate cancer, the von HippelLandau syndrome gene VHL in renal cancer, the mismatch repair gene MLH1 in colon and endometrial cancers, and sometimes BRCA1 in breast cancer (231236). In some of these examples, the same tumor-suppressor gene is mutated or methylated as alternative pathways in the same tumor type: loss-of-function mutations in MLH1 and VHL are found in the germlines of patients with hereditary colon and renal cancer, respectively, and these same genes are hypermethylated and silenced in sporadic tumors of the same histologic type (231,237).

While gain of DNA methylation is often discussed as a late event in tumor progression, CpG hypermethylation in specific sequences often occurs early in cancer formation, sometimes preceding tumorigenesis. Examples of early epigenetic aberrations can also be cited in other adult malignancies: in cigarette smokers, CDKN2A promoter methylation occurs in dysplastic bronchial epithelial cells prior to the formation of overt lung cancers (238), promoter hypermethylation of tumor suppressor genes is already detectable in the pre-malignant lesion Barrett esophagus (239,240). One of the best substantiated examples of a very early epigenetic lesion predisposing to subsequent tumor formation is the gain of methylation of the H19 DMR on the maternal allele, which leads to the loss of imprinting of IGF2 expression and can often be detected in non-neoplastic kidney cells both in BWS-associated and sporadic cases of the pediatric kidney cancer Wilms tumor (227).

DNA hypermethylation has attracted much attention as a biomarker for cancer detection and classification. To be clinically applicable, an ideal tumor biomarker must be specific for cancer, and readily detectable in clinical specimens obtained through minimally invasive procedures. DNA hypermethylation seems to fulfill these requirements and has been considered to be a promising biomarker. Examining the methylation of a subset of genes (GSTP1, APC, RASSF1, and MDR1) distinguished primary prostate cancer from benign prostate tissues with sensitivities and specificities of greater than 90% (241,242). DNA methylation alterations can be detected and used as biomarkers in feces for colorectal cancer, urine for bladder cancer screening, and sputum to predict the occurrence of lung cancer (243245). However, for reasons that are complex but partly financial, these types of tests largely remain at the research stage and have not yet been widely adopted in clinical practice.

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Epigenetics - an overview | ScienceDirect Topics