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Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer

Juliet D. French, Sharon E. Johnatty, Yi Lu, Jonathan Beesley, Bo Gao, Murugan Kalimutho, Michelle J. Henderson, Amanda J. Russell, Siddhartha Kar, Xiaoqing Chen, Kristine M. Hillman, Susanne Kaufmann, Haran Sivakumaran, Martin O’Reilly, Chen Wang, Darren J. Korbie, Australian Ovarian Cancer Study Group, Australian Cancer Study, Diether Lambrechts, Evelyn Despierre, Els Van Nieuwenhuysen, Sandrina Lambrechts, Ignace Vergote, Beth Karlan, Jenny Lester, Sandra Orsulic, Christine Walsh, Peter A. Fasching, Matthias W. Beckmann, Arif B. Ekici, Alexander Hein, Keitaro Matsuo, Satoyo Hosono, Jacobus Pisterer, Peter Hillemanns, Toru Nakanishi, Yasushi Yatabe, Marc T. Goodman, Galina Lurie, Rayna K. Matsuno, Pamela J. Thompson, Tanja Pejovic, Yukie Bean, Florian Heitz, Philipp Harter, Andreas du Bois, Ira Schwaab, Estrid Hogdall, Susanne K. Kjaer, Allan Jensen, Claus Hogdall, Lene Lundvall, Svend Aage Engelholm, Bob Brown, James M. Flanagan, Michelle D. Metcalf, Nadeem Siddiqui, Thomas Sellers, Brooke Fridley, Julie Cunningham, Joellen M. Schildkraut, Ed Iversen, Rachel Palmieri Weber, Donal Brennan, Andrew Berchuck, Paul Pharoah, Paul Harnett, Murray D. Norris, Michelle Haber, Ellen L. Goode, Jason S. Lee, Kum Kum Khanna, Kerstin B. Meyer, Georgia Chenevix-Trench, Anna deFazio, Stacey L. Edwards, Stuart MacGregor _ and on behalf of the Ovarian Cancer Association Consortium

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Oncotarget. 2016; 7:6353-6368. https://doi.org/10.18632/oncotarget.7047

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Abstract

Juliet D. French1,*, Sharon E. Johnatty1,*, Yi Lu1,*, Jonathan Beesley1, Bo Gao2, Murugan Kalimutho1, Michelle J. Henderson3, Amanda J. Russell3, Siddhartha Kar4, Xiaoqing Chen1, Kristine M. Hillman1, Susanne Kaufmann1, Haran Sivakumaran1, Martin O’Reilly5, Chen Wang6, Darren J. Korbie7, Australian Ovarian Cancer Study Group1,2,8, Australian Cancer Study1, Diether Lambrechts9,10, Evelyn Despierre10, Els Van Nieuwenhuysen10, Sandrina Lambrechts10, Ignace Vergote10, Beth Karlan11, Jenny Lester11, Sandra Orsulic11, Christine Walsh11, Peter A. Fasching12,13, Matthias W. Beckmann12, Arif B. Ekici42, Alexander Hein12, Keitaro Matsuo14, Satoyo Hosono14, Jacobus Pisterer15, Peter Hillemanns16, Toru Nakanishi17, Yasushi Yatabe18, Marc T. Goodman19, Galina Lurie20, Rayna K. Matsuno20, Pamela J. Thompson19, Tanja Pejovic21, Yukie Bean21, Florian Heitz22,23, Philipp Harter22,23, Andreas du Bois22,23, Ira Schwaab24, Estrid Hogdall25,26, Susanne K. Kjaer25,27, Allan Jensen25, Claus Hogdall27, Lene Lundvall27, Svend Aage Engelholm28, Bob Brown29, James M. Flanagan29, Michelle D. Metcalf29, Nadeem Siddiqui30, Thomas Sellers31, Brooke Fridley32, Julie Cunningham33, Joellen M. Schildkraut34,35, Ed Iversen36, Rachel Palmieri Weber34, Donal Brennan37, Andrew Berchuck38, Paul Pharoah4,39, Paul Harnett40, Murray D. Norris3, Michelle Haber3, Ellen L. Goode41, Jason S. Lee1, Kum Kum Khanna1, Kerstin B. Meyer5, Georgia Chenevix-Trench1,*,**, Anna deFazio2,*,**, Stacey L. Edwards1,*,**, Stuart MacGregor1,*,** and on behalf of the Ovarian Cancer Association Consortium

1 QIMR Berghofer Medical Research Institute, Brisbane, Australia

2 Department of Gynaecological Oncology and Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Westmead Hospital, Sydney, Australia

3 Children’s Cancer Institute Australia, Randwick, Australia

4 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK

5 Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK

6 Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA

7 Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Australia

8 Peter MacCallum Cancer Centre, Melbourne, Australia

9 Vesalius Research Center, VIB, Leuven, Belgium and Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium

10 Gynecologic Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium

11 Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

12 Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen- Nuremberg, Comprehensive Cancer Center Erlangen-Nuremberg, Erlangen, Germany

13 Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

14 Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan

15 Zentrum für Gynäkologische Onkologie, Kiel, Germany

16 Departments of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany

17 Department of Gynecology, Aichi Cancer Center Central Hospital, Nagoya, Aichi, Japan

18 Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Central Hospital, Nagoya, Aichi, Japan

19 Cancer Prevention and Control Program, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA

20 Cancer Epidemiology Program, University of Hawaii Cancer Center, Hawaii, USA

21 Department of Obstetrics and Gynecology, Oregon Health and Science University and Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA

22 Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany

23 Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, Essen, Germany

24 Institut für Humangenetik Wiesbaden, Germany

25 Danish Cancer Society Research Center, Unit of Virus, Lifestyle and Genes, Copenhagen, Denmark

26 Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark

27 Department of Gynecology, Rigshospitalet, University of Copenhagen, Denmark

28 Department of Oncology, Rigshospitalet, University of Copenhagen, Denmark

29 Department of Surgery and Cancer, Imperial College London, London, UK

30 North Glasgow University Hospitals NHS Trust, Stobhill Hospital, Glasgow, UK

31 Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA

32 Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA

33 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

34 Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA

35 Cancer Control and Population Sciences, Duke Cancer Institute, Durham, NC, USA

36 Department of Statistical Science, Duke University, Durham, NC, USA

37 Queensland Centre for Gynaecological Cancer, Brisbane, Australia

38 Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA

39 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK

40 Crown Princess Mary Cancer Centre and Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Westmead Hospital, Sydney, Australia

41 Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA

42 Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany

* These authors contributed equally to the study and are listed alphabetically

** These authors co-directed the study and are listed alphabetically

Correspondence to:

Georgia Chenevix-Trench, email:

Anna deFazio, email:

Stacey L. Edwards, email:

Stuart MacGregor, email:

Keywords: epithelial ovarian cancer, progression free survival, genome-wide association study, PSIP1, chromosome conformation capture

Received: January 14, 2016 Accepted: January 21, 2016 Published: January 31, 2016

Abstract

Women with epithelial ovarian cancer (EOC) are usually treated with platinum/taxane therapy after cytoreductive surgery but there is considerable inter-individual variation in response. To identify germline single-nucleotide polymorphisms (SNPs) that contribute to variations in individual responses to chemotherapy, we carried out a multi-phase genome-wide association study (GWAS) in 1,244 women diagnosed with serous EOC who were treated with the same first-line chemotherapy, carboplatin and paclitaxel. We identified two SNPs (rs7874043 and rs72700653) in TTC39B (best P=7x10-5, HR=1.90, for rs7874043) associated with progression-free survival (PFS). Functional analyses show that both SNPs lie in a putative regulatory element (PRE) that physically interacts with the promoters of PSIP1, CCDC171 and an alternative promoter of TTC39B. The C allele of rs7874043 is associated with poor PFS and showed increased binding of the Sp1 transcription factor, which is critical for chromatin interactions with PSIP1. Silencing of PSIP1 significantly impaired DNA damage-induced Rad51 nuclear foci and reduced cell viability in ovarian cancer lines. PSIP1 (PC4 and SFRS1 Interacting Protein 1) is known to protect cells from stress-induced apoptosis, and high expression is associated with poor PFS in EOC patients. We therefore suggest that the minor allele of rs7874043 confers poor PFS by increasing PSIP1 expression.


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