Methylation and protein expression of DNA repair genes: association with chemotherapy exposure and survival in sporadic ovarian and peritoneal carcinomas

Abstract

Background: DNA repair genes critically regulate the cellular response to chemotherapy and epigenetic regulation of these genes may be influenced by chemotherapy exposure. Restoration of BRCA1 and BRCA2 mediates resistance to platinum chemotherapy in recurrent BRCA1 and BRCA2 mutated hereditary ovarian carcinomas. We evaluated BRCA1, BRCA2, and MLH1 protein expression in 115 sporadic primary ovarian carcinomas, of which 31 had paired recurrent neoplasms collected after chemotherapy. Additionally, we assessed whether promoter methylation of BRCA1, MLH1 or FANCF influenced response to chemotherapy or explained alterations in protein expression after chemotherapy exposure.

Loss of BRCA1 promotor hypermethylation in recurrent high grade ovarian cancer

“…Accordingly, in a thorough analysis of 489 high-grade serous ovarian cancer samples, the TCGA did also fail to show an impact on OS for BRCA1 methylated tumors [1]. These results have been confirmed by other groups as well [5,9]. Taken together, these results suggest that hypermethylation is either heterogeneous or a dynamic process in ovarian cancer and may not be a good predictor for platinum-based chemotherapy.…”

“…Two of these were covered by our primer set. These sites have been reported to be of particular [7,9,14] expression. CpG site 565 shows also high rates of methylation, however previous studies have shown, that this site is also highly methylated in normal cells [12,16], so that we did not investigate this CpG island.…”

“…The TCGA reported that epigenetic silencing of BRCA1 is mutually exclusive of BRCA1/2 mutations [1]. As results regarding the impact of BRCA1 silencing by promoter hypermethylation on progression free survival (PFS) or OS vary [1,5,9], the stability and clinical significance of this alteration remains currently unclear. The aim of this study was therefore to investigate the stability of BRCA1 promoter hypermethylation in platinum sensitive recurrent disease after platinum based chemotherapy.…”

PLP-Dependent Enzymes: a Potent Therapeutic Approach for Cancer and Cardiovascular Diseases

“…Physiologically, tumors are genetically abnormal cells with uncontrolled rapidly growth and proliferation, for mutation on some genes encoding amino acids metabolizing enzymes, comparing to the corresponding normal cells (Hoffman, 1985). Elevated requirements of methionine are the common biochemical criteria by tumor cells comparing to corresponding normal ones, to fulfill their high protein synthesis and regulation of DNA expression (Stern et al, 1984, Swisher et al, 2009. Practically, hypermethylation of DNA is usually correlates with transcriptional silencing of many of tumor suppressor genes, P 53 genes, thus disrupting DNA repairing systems and cell signaling modulators (Jones andBaylin, 2002, Santini et al, 2001) as reviewed by El-Sayed (2010).…”

“…Practically, hypermethylation of DNA is usually correlates with transcriptional silencing of many of tumor suppressor genes, P 53 genes, thus disrupting DNA repairing systems and cell signaling modulators (Jones andBaylin, 2002, Santini et al, 2001) as reviewed by El-Sayed (2010). Also, methylation of tumor DNA change the identity of CpG islands, thus altering the expression of DNA repairing and apoptosis controlling genes (Sun et al, 1997, Matsukura et al, 2003 and changing of CpG islands (Swisher et al, 2009). On other hand, suppression of methionine synthase genes are a reliable cellular criteria in various cells as bladder, breast, kidney, lung and hematological tumors (Mecham et al, 1983, Hoffman, 1985, Kreis and Goodenow, 1978, thus it described as methionine dependent cells.…”