Epimutations in Cancer

Neoplastic transformation is associated with alterations in DNA methylation, including both global hypomethylation and gene-specific hypermethylation.197-199 Gains of DNA methylation in cancer cells typically reflect hypermethyla-tion of CpG islands in gene promoter regions, which contributes to gene silencing. 1 97 Methylation-dependent gene silencing is a normal mechanism for regulation of gene expression.200 However, in cancer cells methylation-dependent epigenetic gene silencing represents a mutation-independent mechanism for inactivation of tumor suppressor genes or other negative mediators of neoplastic transformation.201 A significant number of cancer-related genes have been identified across all chromosome locations that are subject to methylation-dependent silencing,2 02 and many of these genes contribute to the hallmarks of cancer.203 It is likely that more genes are silenced by hypermethylation than through genetic altera-tions.204 Additionally, some genes that are silenced though epigenetic mechanisms (including DNA methylation) in many tumor types are not subject to genetic mutation.2 04 Similarly, genetic and epigenetic alterations can function together to alter gene expression in cancer cells. There are several examples of genes (MLH1 and p16INK4A) in which one allele is subject to mutation, and subsequently the remaining normal allele becomes silenced through promoter hyper-methylation.204 Thus, epigenetic modifications complement and collaborate with genetic changes to transform normal cells into neoplastic cells. These observations combine to strongly suggest that epigenetic events, and specifically those involving DNA methylation, represent fundamental aspects of cancer and play key roles in neoplastic transformation and progression.

Epimutations in Lung Cancer

Several genes are known to be hypermethylated in lung cancer, resulting in gene silencing.205 Among these genes, p16I NK4A is found to be methylated in more than 40% of lung cancers examined.206,207 Although it is recognized that hyper-methylation of p16I NK4A occurs frequently in lung cancer, there is debate regarding the importance of this mechanism of inactivation among lung cancer patients who are smokers versus nonsmokers (or never smokers). In one study, deletion or mutation of the p16I NK4A gene was only observed in the lung cancers of smokers, while hypermethylation was found only among nonsmokers.208 In contrast, other studies have found hypermethylation of p16I NK4A as the prevalent mechanism of inactivation among lung cancers from smok-ers.209 Other epigenetically regulated genes in lung cancer include CDH1,210 CDKN1A,211 DAPK1,212 ESR1,213 GJB2,214 GSTP1,215 HS3ST2,216 PRDM2,217 PRKCDBP,218 RASSF1,219 and SFN.120 Similar to p16™K4A1 RASSF1 may be subject to inactivation through multiple molecular mechanisms:

hypermethylation219 and deletion of chromosome 3p21.54 Using recently developed array-based methods, a number of putative targets for promoter methylation in lung cancer (including some new gene targets) have been identified, including HIC1, IRF7, ASC, RIPK3, FABP3, and PAX3.221

Epimutations in Colorectal Cancer

Methylation of multiple gene targets occurs during colo-rectal carcinogenesis and some of these methylation events occur early in the multistep process. HLTF, hMLHl, MGMT, APC, and ATM are frequently methylated in colorectal adenomas (42-78%), at least one of these genes was methylated in 100% of the adenomas tested, and 61% contained at least three methylated genes.222 Similarly, another study found that p16INK4A, MGMT, and hMLHl are methylated in 34%, 49%, and 7% of colorectal adenomas, respectively.223 These genes were not methylated in normal colonic mucosa and were infrequently methylated in hyperplastic polyps (5%, 10%, and 7.5%, respectively).223 These observations suggest that methylation events that occur early in colorectal tumori-genesis may significantly contribute to progression of pre-neoplastic lesions toward malignant conversion. In fact, the methylation patterns observed in colorectal adenomas are preserved with progression to colorectal carcinoma. HLTF, hMLH1, MGMT, APC, and ATM are methylated in colorectal carcinomas with similar or greater frequency (47-77%) compared to that observed in adenomas, and 68% contain at least three methylated genes.222

Epimutations in Breast and Prostate Cancer

A number of studies have shown the presence of aberrant DNA methylation of genes in breast carcinogenesis, affecting genes including p16™K4A, p14ARF, Cyclin D2, and Slit2.224 The majority (86%) of breast tumors showed hypermethyla-tion of at least one gene, and there was a significant correlation between methylation in tumor and serum DNA of all genes.224 In other studies, nipple aspiration was applied as a noninvasive technique to obtain DNA samples for examination of tumor-associated gene methylation.225 Hyperm-ethylation of one or more genes, including GSTP1, RARP2, p16™K4A, p14ARF, RASSF1, and DAP-kinase, was detected in DNA from nipple aspirate, and identical gene hypermeth-ylation was found in 82% of matched breast tumor tissue samples.225 However, no aberrant levels of gene methylation were seen in the normal and benign breast tissue or in nipple aspirates from healthy women.225 Several studies have examined methylation of GSTP1 in prostate cancers.226 Hypermethylation of GSTP1 has been analyzed in more than 1,000 prostate tumor samples and has been shown to be methylated in the majority (81%) of these tumors. In addition, a recent study of GSTP1, ARF, p16INK4A, and MGMT methyla-tion levels in urine sediments reported that these four genes were able to identify the majority (87%) of prostate cancer patients with extremely high specificity (100%) compared to control samples.227 These findings suggest that DNA from urine samples could be utilized as a screening tool to reduce the number of biopsies performed on men with a high risk of developing prostate cancer.226

Epimutations in Other Cancers

In addition to the major cancer sites described here, aberrant epigenetic regulation of gene expression has been documented in various other human cancers, including cancers of the oral cavity,228 cervix,229 ovary,230 skin,231 pancreas,232 and brain,233 and leukemia234 and lymphoma.235

The Smoker's Sanctuary

The Smoker's Sanctuary

Save Your Lungs And Never Have To Spend A Single Cent Of Ciggies Ever Again. According to a recent report from the U.S. government. Centers for Disease Control and Prevention, more than twenty percent of male and female adults in the U.S. smoke cigarettes, while more than eighty percent of them light up a cigarette daily.

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