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. 2017 May 1;23(9):2213-2222.
doi: 10.1158/1078-0432.CCR-16-1754. Epub 2016 Sep 23.

Platinum-Based Chemotherapy Induces Methylation Changes in Blood DNA Associated with Overall Survival in Patients with Ovarian Cancer

James M Flanagan  1 , Angela Wilson  1 , Chail Koo  1 , Nahal Masrour  1 , John Gallon  1 , Erick Loomis  1 , Kirsty Flower  1 , Charlotte Wilhelm-Benartzi  1 , Alexander Hergovich  2 , Paula Cunnea  1 , Hani Gabra  1 , Elena Ioana Braicu  3   4 , Jalid Sehouli  3   4 , Silvia Darb-Esfahani  4   5 , Adriaan Vanderstichele  6 , Ignace Vergote  6 , Caroline Kreuzinger  7 , Dan Cacsire Castillo-Tong  7 , G Bea A Wisman  8 , Els Mjj Berns  9 , Nadeem Siddiqui  10 , James Paul  11 , Robert Brown  12   13
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Free article

Platinum-Based Chemotherapy Induces Methylation Changes in Blood DNA Associated with Overall Survival in Patients with Ovarian Cancer

James M Flanagan et al. Clin Cancer Res. .
Free article

Abstract

Purpose: DNA damage repair can lead to epigenetic changes. DNA mismatch repair proteins bind to platinum DNA adducts and at sites of DNA damage can recruit the DNA methylating enzyme DNMT1, resulting in aberrant methylation. We hypothesised that DNA damage repair during platinum-based chemotherapy may cause aberrant DNA methylation in normal tissues of patients such as blood.Experimental Design: We used Illumina 450k methylation arrays and bisulphite pyrosequencing to investigate methylation at presentation and relapse in blood DNA from patients with ovarian cancer enrolled in the SCOTROC1 trial (n = 247) and in a cohort of ovarian tumor DNA samples collected at first relapse (n = 46). We used an ovarian cancer cell line model to investigate the role of the DNA mismatch repair gene MLH1 in platinum-induced methylation changes.Results: Specific CpG methylation changes in blood at relapse are observed following platinum-based chemotherapy and are associated with patient survival, independent of other clinical factors [hazard ratio, 3.7; 95% confidence interval, 1.8-7.6, P = 2.8 × 10-4]. Similar changes occur in ovarian tumors at relapse, also associated with patient survival (hazard ratio, 2.6; 95% confidence interval, 1.0-6.8, P = 0.048). Using an ovarian cancer cell line model, we demonstrate that functional mismatch repair increases the frequency of platinum-induced methylation.Conclusions: DNA methylation in blood at relapse following chemotherapy, and not at presentation, is informative regarding survival of patients with ovarian cancer. Functional DNA mismatch repair increases the frequency of DNA methylation changes induced by platinum. DNA methylation in blood following chemotherapy could provide a noninvasive means of monitoring patients' epigenetic responses to treatment without requiring a tumor biopsy. Clin Cancer Res; 23(9); 2213-22. ©2016 AACR.

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