The Acquisition of hMLH1 Methylation in Plasma DNA after Chemotherapy Predicts Poor Survival for Ovarian Cancer Patients

Abstract

Aberrant epigenetic regulation, such as CpG island methylation and associated transcriptional silencing of genes, has been implicated in a variety of human diseases, including cancer. Methylation of genes involved in apoptosis, including the DNA mismatch repair (MMR) gene hMLH1, can occur in tumor models of resistance to chemotherapeutic drugs. However, the relevance for acquired resistance to chemotherapy of patients' tumors remains unsubstantiated. Plasma DNA from cancer patients, including those with ovarian cancer, often contains identical DNA changes as the tumor and provides a means to monitor CpG island methylation changes. We have examined plasma DNA of patients with epithelial ovarian cancer enrolled in the SCOTROC1 Phase III clinical trial for methylation of the hMLH1 CpG island before carboplatin/taxoid chemotherapy and at relapse. Methylation of hMLH1 is increased at relapse, and 25% (34 of 138) of relapse samples have hMLH1 methylation that is not detected in matched prechemotherapy plasma samples. Furthermore, hMLH1 methylation is significantly associated with increased microsatellite instability in plasma DNA at relapse, providing an independent measure of function of the MMR pathway. Acquisition of hMLH1 methylation in plasma DNA at relapse predicts poor overall survival of patients, independent from time to progression and age (hazard ratio, 1.99; 95% confidence interval, 1.20 -3.30; P ‫؍‬ 0.007). These data support the clinical relevance of acquired hMLH1 methylation and concomitant loss of DNA MMR after chemotherapy of ovarian cancer patients. DNA methylation changes in plasma provide the potential to define patterns of methylation during therapy and identify those patient populations who would be suitable for novel epigenetic therapies.

MLH1 expression sensitises ovarian cancer cells to cell death mediated by XIAP inhibition

“…Indeed, studies link MMR deficiency with reduced CR to platinumbased chemotherapy (Fink et al, 1998b;Strathdee et al, 2001;Gifford et al, 2004). In this study, microarray expression data from 54 patients with advanced stage serous EOC, who had received either cisplatin or carboplatin as part of their primary chemotherapeutic treatment, revealed a correlation between a high MLH1 expression in the patients' tumours and increased CR and survival.…”

Epigenetic silencing of HSulf-1 in ovarian cancer:implications in chemoresistance

“…Several genes involved in apoptotic pathways related to chemotherapeutic action in ovarian cancer are downregulated by epigenetic mechanisms (Makarla et al, 2005). Methylation of specific genes such as hMLH1 has been shown to correlate with the onset of tumor relapse after carboplatin/taxol therapy in ovarian cancer patients (Gifford et al, 2004). In addition, treatment of cisplatin-resistant A2780/CP ovarian cancer cells with 5-aza-dC induced the expression of hMLH1 and resensitized these cells to cisplatin in a mouse xenograft model (Plumb et al, 2000).…”

Promoter hypermethylation of FANCF and outcome in advanced ovarian cancer

“…For example, if the Taniguchi model were correct, the predicted effect of the use of nonselective demethylating agents would be to reactivate FANCF expression, and thereby increase cellular resistance to cisplatin. Conversely, Gifford et al (2004) have clearly shown that acquired methylation of hMLH1 is associated with clinical resistance to cisplatin-based chemotherapy.…”