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Clin Cancer Res. 2015 Dec 1;21(23):5264-76. doi: 10.1158/1078-0432.CCR-15-0632. Epub 2015 Jul 7.

Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes: Findings from the Ovarian Cancer Association Consortium.

Author information

1
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
2
Department of Oncology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, United Kingdom.
3
Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia. Center for Cancer Research, University of Sydney at Westmead Millennium Institute, Sydney, New South Wales, Australia.
4
Division of Hematology and Oncology, Department of Medicine, University of California at Los Angeles, David Geffen School of Medicine, Los Angeles, California. University Hospital Erlangen, Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
5
University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
6
University Hospital Erlangen, Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
7
Vesalius Research Center, VIB, Leuven, Belgium. Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
8
Department of Gynecologic Oncology, Leuven Cancer Institute, University of Leuven, Leuven, Belgium.
9
Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington. Department of Epidemiology, University of Washington, Seattle, Washington.
10
Department of Community and Family Medicine, Section of Biostatistics and Epidemiology, The Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
11
German Cancer Research Center (DKFZ), Division of Cancer Epidemiology, Heidelberg, Germany.
12
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania. Women's Cancer Research Program, Magee-Women's Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
13
The University of Texas School of Public Health, Houston, Texas.
14
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York.
15
Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York.
16
Radboud University Medical Centre, Radboud Institute for Health Sciences, Nijmegen, the Netherlands.
17
Radboud University Medical Centre, Radboud Institute for Molecular Sciences, Nijmegen, the Netherlands.
18
International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
19
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
20
Department of Cancer Epidemiology and Prevention, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
21
Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, United Kingdom.
22
Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
23
Faculty of Medicine, University of Southampton, University Hospital Southampton, Southampton, Hampshire, United Kingdom.
24
Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, California.
25
Epidemiology Center, College of Medicine, University of South Florida, Tampa, Florida.
26
Department of Epidemiology, Center for Cancer Genetics Research and Prevention, School of Medicine, University of California Irvine, Irvine, California.
27
Department of Epidemiology, University of California Irvine, Irvine, California.
28
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California.
29
Women's Cancer, UCL EGA Institute for Women's Health, London, United Kingdom.
30
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California. Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan.
31
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York.
32
Department of Pathology and Laboratory Diagnostics, The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
33
Department of Gynecologic Oncology, The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
34
Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California. Community and Population Health Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California.
35
Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
36
Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, Essen, Germany. Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany.
37
Institut für Humangenetik Wiesbaden, Wiesbaden, Germany.
38
Zentrum für Gynäkologische Onkologie, Kiel, Germany.
39
Department of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany.
40
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
41
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
42
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark. Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
43
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
44
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark. Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
45
Biostatistics and Informatics Shared Resource, University of Kansas Medical Center, Kansas City, Kansas.
46
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
47
Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina. Cancer Control and Population Sciences, Duke Cancer Institute, Durham, North Carolina.
48
Department of Statistical Science, Duke University, Durham, North Carolina.
49
Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Harvard School of Public Health, Boston, Massachusetts.
50
Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, The State University of New Jersey, New Brunswick, New Jersey.
51
Memorial Sloan Kettering Cancer Center, Department of Epidemiology and Biostatistics, Epidemiology Service, New York, New York.
52
Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, Oregon. Knight Cancer Institute, Portland, Oregon.
53
Department of Gynaecology, The Juliane Marie Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
54
Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Beatson Institute for Cancer Research, Glasgow, United Kingdom.
55
Cancer Research UK Clinical Trials Unit, Glasgow, The Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom.
56
Department of Gynaecological Oncology, Glasgow Royal Infirmary, Glasgow, United Kingdom.
57
Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida.
58
Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina.
59
Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
60
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. georgia.trench@qimrberghofer.edu.au.

Abstract

PURPOSE:

Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome.

EXPERIMENTAL DESIGN:

We analyzed approximately 2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent first-line treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with ≥ 4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients, including patients from The Cancer Genome Atlas. In addition, we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis.

RESULTS:

Five SNPs were significantly associated (P ≤ 1.0 × 10(-5)) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23), and rs6674079 (1q22), were located in long noncoding RNAs (lncRNAs) RP11-179A10.1, RP11-314O13.1, and RP11-284F21.8, respectively (P ≤ 7.1 × 10(-6)). ENCODE ChIP-seq data at 1q22 for normal ovary show evidence of histone modification around RP11-284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression and high-density lipoprotein (HDL)-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA ≤ 6 × 10(-3)).

CONCLUSIONS:

We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies.

PMID:
26152742
PMCID:
PMC4624261
DOI:
10.1158/1078-0432.CCR-15-0632
[Indexed for MEDLINE]
Free PMC Article

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