title: 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.
authors.affiliation: Centre for Oncology and Applied Pharmacology, Glasgow University, Cancer Research UK Beatson Laboratories, Glasgow, United Kingdom.
authors.forename: Gillian
authors.initials: G
authors.lastname: Gifford
authors.forename: Jim
authors.initials: J
authors.lastname: Paul
authors.forename: Paul A
authors.initials: PA
authors.lastname: Vasey
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Kaye
authors.forename: Robert
authors.initials: R
authors.lastname: Brown
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000483:Alleles; D016190:Carboplatin / Q000627:therapeutic use; D002352:Carrier Proteins; D018899:CpG Islands; D004247:DNA / Q000097:blood* / Q000378:metabolism; D019175:DNA Methylation; D018450:Disease Progression; D005260:Female; D020868:Gene Silencing; D006801:Humans; D018895:Microsatellite Repeats; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D009687:Nuclear Proteins; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism; D017239:Paclitaxel / Q000627:therapeutic use; D016133:Polymerase Chain Reaction; D016016:Proportional Hazards Models; D011897:Random Allocation; D012008:Recurrence; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D004247:DNA; D016190:Carboplatin; D000070957:MutL Protein Homolog 1; D017239:Paclitaxel