Platinum-Based Chemotherapy Induces Methylation Changes in Blood DNA Associated with Overall Survival in Patients with Ovarian Cancer.
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 geneMLH1in 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.
Department of Surgery and Cancer, Imperial College London, London, UK.
James M
JM
Flanagan
Department of Surgery and Cancer, Imperial College London, London, UK.
Angela
A
Wilson
Department of Surgery and Cancer, Imperial College London, London, UK.
Chail
C
Koo
Department of Surgery and Cancer, Imperial College London, London, UK.
Nahal
N
Masrour
Department of Surgery and Cancer, Imperial College London, London, UK.
John
J
Gallon
Department of Surgery and Cancer, Imperial College London, London, UK.
Erick
E
Loomis
Department of Surgery and Cancer, Imperial College London, London, UK.
Kirsty
K
Flower
Department of Surgery and Cancer, Imperial College London, London, UK.
Charlotte
C
Wilhelm-Benartzi
UCL Cancer Institute, UCL, London, UK.
Alexander
A
Hergovich
Department of Surgery and Cancer, Imperial College London, London, UK.
Paula
P
Cunnea
Department of Surgery and Cancer, Imperial College London, London, UK.
Hani
H
Gabra
Department of Gynecology, European Competence Center for Ovarian Cancer; Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany.|Tumorbank Ovarian Cancer Network (TOC), Berlin, Germany.
Elena Ioana
EI
Braicu
Department of Gynecology, European Competence Center for Ovarian Cancer; Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany.|Tumorbank Ovarian Cancer Network (TOC), Berlin, Germany.
Jalid
J
Sehouli
Tumorbank Ovarian Cancer Network (TOC), Berlin, Germany.|Institute of Pathology, Charitéplatz, Berlin, Germany.
Silvia
S
Darb-Esfahani
Division of Gynaecological Oncology, Department of Obstetrics and Gynaecology, Universitaire Ziekenhuizen Leuven, Katholieke Universiteit Leuven, Leuven, Belgium.
Adriaan
A
Vanderstichele
Division of Gynaecological Oncology, Department of Obstetrics and Gynaecology, Universitaire Ziekenhuizen Leuven, Katholieke Universiteit Leuven, Leuven, Belgium.
Ignace
I
Vergote
Translational Gynecology Group, Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
Caroline
C
Kreuzinger
Translational Gynecology Group, Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
Dan Cacsire
DC
Castillo-Tong
Department of Gynecologic Oncology, Cancer Research Center Groningen, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
G Bea A
GBA
Wisman
Erasmus MC Cancer Institute, Department of Medical Oncology, Rotterdam, the Netherlands.
Els Mjj
EM
Berns
Department of Gynaecological Oncology, Glasgow Royal Infirmary, Glasgow, UK.
Nadeem
N
Siddiqui
Cancer Research UK Clinical Trials Unit, Institute of Cancer Sciences, University of Glasgow, UK.
James
J
Paul
Department of Surgery and Cancer, Imperial College London, London, UK. E-mail:b.brown@imperial.ac.uk.|Section of Molecular Pathology, Institute for Cancer Research, Sutton, UK.
Robert
R
Brown
D000368:Aged; D045744:Cell Line, Tumor; D018736:DNA Adducts / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics*; D004260:DNA Repair / Q000187:drug effects; D004273:DNA, Neoplasm / Q000097:blood* / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010984:Platinum / Q000008:administration & dosage* / Q000009:adverse effects; D011401:Promoter Regions, Genetic
D018736:DNA Adducts; D004273:DNA, Neoplasm; D010984:Platinum