title: Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer.
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.
authors: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors: Juliet D
authors: JD
authors: French
authors: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors: Sharon E
authors: SE
authors: Johnatty
authors: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors: Yi
authors: Y
authors: Lu
authors: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors: Jonathan
authors: J
authors: Beesley
authors: Department of Gynaecological Oncology and Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Westmead Hospital, Sydney, Australia.
authors: Bo
authors: B
authors: Gao
authors: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors: Murugan
authors: M
authors: Kalimutho
authors: Children's Cancer Institute Australia, Randwick, Australia.
authors: Michelle J
authors: MJ
authors: Henderson
authors: Children's Cancer Institute Australia, Randwick, Australia.
authors: Amanda J
authors: AJ
authors: Russell
authors: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors: Siddhartha
authors: S
authors: Kar
authors: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors: Xiaoqing
authors: X
authors: Chen
authors: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors: Kristine M
authors: KM
authors: Hillman
authors: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors: Susanne
authors: S
authors: Kaufmann
authors: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors: Haran
authors: H
authors: Sivakumaran
authors: Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK.
authors: Martin
authors: M
authors: O'Reilly
authors: Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA.
authors: Chen
authors: C
authors: Wang
authors: Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Australia.
authors: Darren J
authors: DJ
authors: Korbie
authors: Vesalius Research Center, VIB, Leuven, Belgium and Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.|Gynecologic Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
authors: Diether
authors: D
authors: Lambrechts
authors: Gynecologic Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
authors: Evelyn
authors: E
authors: Despierre
authors: Gynecologic Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
authors: Els
authors: E
authors: Van Nieuwenhuysen
authors: Gynecologic Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
authors: Sandrina
authors: S
authors: Lambrechts
authors: Gynecologic Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
authors: Ignace
authors: I
authors: Vergote
authors: Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: Beth
authors: B
authors: Karlan
authors: Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: Jenny
authors: J
authors: Lester
authors: Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: Sandra
authors: S
authors: Orsulic
authors: Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: Christine
authors: C
authors: Walsh
authors: Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-Nuremberg, Erlangen, Germany.|Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors: Peter A
authors: PA
authors: Fasching
authors: Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-Nuremberg, Erlangen, Germany.
authors: Matthias W
authors: MW
authors: Beckmann
authors: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors: Arif B
authors: AB
authors: Ekici
authors: Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-Nuremberg, Erlangen, Germany.
authors: Alexander
authors: A
authors: Hein
authors: Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan.
authors: Keitaro
authors: K
authors: Matsuo
authors: Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan.
authors: Satoyo
authors: S
authors: Hosono
authors: Zentrum für Gynäkologische Onkologie, Kiel, Germany.
authors: Jacobus
authors: J
authors: Pisterer
authors: Departments of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany.
authors: Peter
authors: P
authors: Hillemanns
authors: Department of Gynecology, Aichi Cancer Center Central Hospital, Nagoya, Aichi, Japan.
authors: Toru
authors: T
authors: Nakanishi
authors: Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Central Hospital, Nagoya, Aichi, Japan.
authors: Yasushi
authors: Y
authors: Yatabe
authors: Cancer Prevention and Control Program, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA.
authors: Marc T
authors: MT
authors: Goodman
authors: Cancer Epidemiology Program, University of Hawaii Cancer Center, Hawaii, USA.
authors: Galina
authors: G
authors: Lurie
authors: Cancer Epidemiology Program, University of Hawaii Cancer Center, Hawaii, USA.
authors: Rayna K
authors: RK
authors: Matsuno
authors: Cancer Prevention and Control Program, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA.
authors: Pamela J
authors: PJ
authors: Thompson
authors: Department of Obstetrics and Gynecology, Oregon Health and Science University and Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
authors: Tanja
authors: T
authors: Pejovic
authors: Department of Obstetrics and Gynecology, Oregon Health and Science University and Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
authors: Yukie
authors: Y
authors: Bean
authors: Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany.|Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, Essen, Germany.
authors: Florian
authors: F
authors: Heitz
authors: Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany.|Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, Essen, Germany.
authors: Philipp
authors: P
authors: Harter
authors: Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany.|Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, Essen, Germany.
authors: Andreas
authors: A
authors: du Bois
authors: Institut für Humangenetik Wiesbaden, Germany.
authors: Ira
authors: I
authors: Schwaab
authors: Danish Cancer Society Research Center, Unit of Virus, Lifestyle and Genes, Copenhagen, Denmark.|Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
authors: Estrid
authors: E
authors: Hogdall
authors: Danish Cancer Society Research Center, Unit of Virus, Lifestyle and Genes, Copenhagen, Denmark.|Department of Gynecology, Rigshospitalet, University of Copenhagen, Denmark.
authors: Susanne K
authors: SK
authors: Kjaer
authors: Danish Cancer Society Research Center, Unit of Virus, Lifestyle and Genes, Copenhagen, Denmark.
authors: Allan
authors: A
authors: Jensen
authors: Department of Gynecology, Rigshospitalet, University of Copenhagen, Denmark.
authors: Claus
authors: C
authors: Hogdall
authors: Department of Gynecology, Rigshospitalet, University of Copenhagen, Denmark.
authors: Lene
authors: L
authors: Lundvall
authors: Department of Oncology, Rigshospitalet, University of Copenhagen, Denmark.
authors: Svend Aage
authors: SA
authors: Engelholm
authors: Department of Surgery and Cancer, Imperial College London, London, UK.
authors: Bob
authors: B
authors: Brown
authors: Department of Surgery and Cancer, Imperial College London, London, UK.
authors: James M
authors: JM
authors: Flanagan
authors: Department of Surgery and Cancer, Imperial College London, London, UK.
authors: Michelle D
authors: MD
authors: Metcalf
authors: North Glasgow University Hospitals NHS Trust, Stobhill Hospital, Glasgow, UK.
authors: Nadeem
authors: N
authors: Siddiqui
authors: Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
authors: Thomas
authors: T
authors: Sellers
authors: Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA.
authors: Brooke
authors: B
authors: Fridley
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors: Julie
authors: J
authors: Cunningham
authors: Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA.|Cancer Control and Population Sciences, Duke Cancer Institute, Durham, NC, USA.
authors: Joellen M
authors: JM
authors: Schildkraut
authors: Department of Statistical Science, Duke University, Durham, NC, USA.
authors: Ed
authors: E
authors: Iversen
authors: Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA.
authors: Rachel Palmieri
authors: RP
authors: Weber
authors: Queensland Centre for Gynaecological Cancer, Brisbane, Australia.
authors: Donal
authors: D
authors: Brennan
authors: Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA.
authors: Andrew
authors: A
authors: Berchuck
authors: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.|Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
authors: Paul
authors: P
authors: Pharoah
authors: Crown Princess Mary Cancer Centre and Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Westmead Hospital, Sydney, Australia.
authors: Paul
authors: P
authors: Harnett
authors: Children's Cancer Institute Australia, Randwick, Australia.
authors: Murray D
authors: MD
authors: Norris
authors: Children's Cancer Institute Australia, Randwick, Australia.
authors: Michelle
authors: M
authors: Haber
authors: Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
authors: Ellen L
authors: EL
authors: Goode
authors: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors: Jason S
authors: JS
authors: Lee
authors: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors: Kum Kum
authors: KK
authors: Khanna
authors: Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK.
authors: Kerstin B
authors: KB
authors: Meyer
authors: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors: Georgia
authors: G
authors: Chenevix-Trench
authors: Department of Gynaecological Oncology and Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Westmead Hospital, Sydney, Australia.
authors: Anna
authors: A
authors: deFazio
authors: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors: Stacey L
authors: SL
authors: Edwards
authors: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors: Stuart
authors: S
authors: MacGregor
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D015331:Cohort Studies; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000473:pathology; D024202:Electrophoretic Mobility Shift Assay; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005185:Fallopian Tube Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014157:Transcription Factors / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; C504649:PSIP1 protein, human; D012333:RNA, Messenger; D014157:Transcription Factors
keywords: PSIP1; chromosome conformation capture; epithelial ovarian cancer; genome-wide association study; progression free survival