Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31

Jennifer Permuth-Wey (), Kate Lawrenson, Howard C. Shen, Aneliya Velkova, Jonathan P. Tyrer, Zhihua Chen, Hui-Yi Lin, Y Ann Chen, Ya-Yu Tsai, Xiaotao Qu, Susan J. Ramus, Rod Karevan, Janet Lee, Nathan Lee, Melissa C. Larson, Katja K. Aben, Hoda Anton-Culver, Natalia Antonenkova, Antonis C. Antoniou, Sebastian M. Armasu, François Bacot, Laura Baglietto, Elisa V. Bandera, Jill Barnholtz-Sloan, Matthias W. Beckmann, Michael J. Birrer, Greg Bloom, Natalia Bogdanova, Louise A. Brinton, Angela Brooks-Wilson, Robert Brown, Ralf Butzow, Qiuyin Cai, Ian Campbell, Jenny Chang-Claude, Stephen Chanock, Georgia Chenevix-Trench, Jin Q. Cheng, Mine S. Cicek, Gerhard A. Coetzee, Linda S. Cook, Fergus J. Couch, Daniel W. Cramer, Julie M. Cunningham, Agnieszka Dansonka-Mieszkowska, Evelyn Despierre, Jennifer A. Doherty, Thilo Dörk, Andreas du Bois, Matthias Dürst, Douglas F. Easton, Diana Eccles, Robert Edwards, Arif B. Ekici, Peter A. Fasching, David A. Fenstermacher, James M. Flanagan, Montserrat Garcia-Closas, Aleksandra Gentry-Maharaj, Graham G. Giles, Rosalind M. Glasspool, Jesus Gonzalez-Bosquet, Marc T. Goodman, Martin Gore, Bohdan Górski, Jacek Gronwald, Per Hall, Mari K. Halle, Philipp Harter, Florian Heitz, Peter Hillemanns, Maureen Hoatlin, Claus K. Høgdall, Estrid Høgdall, Satoyo Hosono, Anna Jakubowska, Allan Jensen, Heather Jim, Kimberly R. Kalli, Beth Y. Karlan, Stanley B. Kaye, Linda E. Kelemen, Lambertus A. Kiemeney, Fumitaka Kikkawa, Gottfried E. Konecny, Camilla Krakstad, Susanne Krüger Kjaer, Jolanta Kupryjanczyk, Diether Lambrechts, Sandrina Lambrechts, Johnathan M. Lancaster, Nhu D. Le, Arto Leminen, Douglas A. Levine, Dong Liang, Boon Kiong Lim, Jie Lin, Jolanta Lissowska, Karen H. Lu, Jan Lubiński, Galina Lurie, Leon F.A.G Massuger, Keitaro Matsuo, Valerie McGuire, John R. McLaughlin, Usha Menon, Francesmary Modugno, Kirsten B. Moysich, Toru Nakanishi, Steven A. Narod, Lotte Nedergaard, Roberta B. Ness, Heli Nevanlinna, Stefan Nickels, Houtan Noushmehr, Kunle Odunsi, Sara H. Olson, Irene Orlow, James Paul, Celeste L. Pearce, Tanja Pejovic, Liisa M. Pelttari, Malcolm C. Pike, Elizabeth M. Poole, Paola Raska, Stefan P. Renner, Harvey A. Risch, Lorna Rodriguez-Rodriguez, Mary Anne Rossing, Anja Rudolph, Ingo B. Runnebaum, Iwona K. Rzepecka, Helga B. Salvesen, Ira Schwaab, Gianluca Severi, Viji Shridhar, Xiao-Ou Shu, Yurii B. Shvetsov, Weiva Sieh, Honglin Song, Melissa C. Southey, Beata Spiewankiewicz, Daniel Stram, Rebecca Sutphen, Soo-Hwang Teo, Kathryn L. Terry, Daniel C. Tessier, Pamela J. Thompson, Shelley S. Tworoger, Anne M. van Altena, Ignace Vergote, Robert A. Vierkant, Daniel Vincent, Allison F. Vitonis, Shan Wang-Gohrke, Rachel Palmieri Weber, Nicolas Wentzensen, Alice S. Whittemore, Elisabeth Wik, Lynne R. Wilkens, Boris Winterhoff, Yin Ling Woo, Anna H. Wu, Yong-Bing Xiang, Hannah P. Yang, Wei Zheng, Argyrios Ziogas, Famida Zulkifli, Catherine M. Phelan, Edwin Iversen, Joellen M. Schildkraut, Andrew Berchuck, Brooke L. Fridley, Ellen L. Goode, Paul D.P. Pharoah, Alvaro N.A. Monteiro, Thomas A. Sellers () and Simon A. Gayther ()
Additional contact information
Jennifer Permuth-Wey: Moffitt Cancer Center, Tampa
Kate Lawrenson: Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles
Howard C. Shen: Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles
Aneliya Velkova: Moffitt Cancer Center, Tampa
Jonathan P. Tyrer: University of Cambridge
Zhihua Chen: Moffitt Cancer Center
Hui-Yi Lin: Moffitt Cancer Center
Y Ann Chen: Moffitt Cancer Center
Ya-Yu Tsai: Moffitt Cancer Center, Tampa
Xiaotao Qu: Moffitt Cancer Center
Susan J. Ramus: Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles
Rod Karevan: Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles
Janet Lee: Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles
Nathan Lee: Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles
Melissa C. Larson: Mayo Clinic
Katja K. Aben: Biostatistics and HTA, Radboud University Medical Centre
Hoda Anton-Culver: Director of Genetic Epidemiology Research Institute, UCI Center of Medicine, University of California Irvine
Natalia Antonenkova: Byelorussian Institute for Oncology and Medical Radiology Aleksandrov N.N.
Antonis C. Antoniou: Centre for Cancer Genetic Epidemiology, University of Cambridge
Sebastian M. Armasu: Mayo Clinic
François Bacot: McGill University and Génome Québec Innovation Centre
Laura Baglietto: Cancer Epidemiology Centre, The Cancer Council Victoria
Elisa V. Bandera: The Cancer Institute of New Jersey, Robert Wood Johnson Medical School
Jill Barnholtz-Sloan: Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine
Matthias W. Beckmann: University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center
Michael J. Birrer: Massachusetts General Hospital
Greg Bloom: Moffitt Cancer Center
Natalia Bogdanova: Gynaecology Research Unit, Hannover Medical School
Louise A. Brinton: National Cancer Institute
Angela Brooks-Wilson: Genome Sciences Centre, BC Cancer Agency
Robert Brown: Imperial College London
Ralf Butzow: University of Helsinki and Helsinki University Central Hospital
Qiuyin Cai: Vanderbilt Epidemiology Center and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine
Ian Campbell: Peter MacCallum Cancer Centre
Jenny Chang-Claude: German Cancer Research Center
Stephen Chanock: National Cancer Institute
Georgia Chenevix-Trench: Cancer Genetics Laboratory, Queensland Institute of Medical Research
Jin Q. Cheng: Moffitt Cancer Center
Mine S. Cicek: Mayo Clinic College of Medicine
Gerhard A. Coetzee: Microbiology and Preventive Medicine, University of Southern California, Norris Comprehensive Cancer Center
Linda S. Cook: University of New Mexico
Fergus J. Couch: Mayo Clinic
Daniel W. Cramer: Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School
Julie M. Cunningham: Mayo Clinic
Agnieszka Dansonka-Mieszkowska: The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology
Evelyn Despierre: University Hospitals Leuven
Jennifer A. Doherty: Section of Biostatistics and Epidemiology, The Geisel School of Medicine at Dartmouth
Thilo Dörk: Gynaecology Research Unit, Hannover Medical School
Andreas du Bois: Dr. Horst Schmidt Klinik Wiesbaden
Matthias Dürst: Jena University Hospital
Douglas F. Easton: Centre for Cancer Genetic Epidemiology, University of Cambridge
Diana Eccles: Faculty of Medicine, University of Southampton, University Hospital Southampton
Robert Edwards: Maggee Women's Hospital
Arif B. Ekici: Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg
Peter A. Fasching: University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center
David A. Fenstermacher: Moffitt Cancer Center
James M. Flanagan: Imperial College London
Montserrat Garcia-Closas: Sections of Epidemiology and Genetics at the Institute of Cancer Research and Breakthrough Breast Cancer Research Centre
Aleksandra Gentry-Maharaj: Gynaecological Cancer Research Centre, Women’s Cancer, Institute for Women's Health, University College London
Graham G. Giles: Cancer Epidemiology Centre, The Cancer Council Victoria
Rosalind M. Glasspool: The Beatson West of Scotland Cancer Centre
Jesus Gonzalez-Bosquet: Moffitt Cancer Center
Marc T. Goodman: Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center
Martin Gore: Gynecological Oncology Unit, The Royal Marsden Hospital
Bohdan Górski: International Hereditary Cancer Center, Pomeranian Medical University
Jacek Gronwald: International Hereditary Cancer Center, Pomeranian Medical University
Per Hall: Karolinska Istitutet
Mari K. Halle: Haukeland University Hospital
Philipp Harter: Dr. Horst Schmidt Klinik Wiesbaden
Florian Heitz: Dr. Horst Schmidt Klinik Wiesbaden
Peter Hillemanns: Clinics of Obstetrics and Gynaecology, Hannover Medical School
Maureen Hoatlin: Oregon Health and Science University
Claus K. Høgdall: The Juliane Marie Centre
Estrid Høgdall: Molecular Unit, Herlev Hospital, University of Copenhagen
Satoyo Hosono: Aichi Cancer Center Research Institute
Anna Jakubowska: International Hereditary Cancer Center, Pomeranian Medical University
Allan Jensen: Virus, Lifestyle and Genes, Danish Cancer Society Research Center
Heather Jim: Moffitt Cancer Center
Kimberly R. Kalli: Mayo Clinic
Beth Y. Karlan: Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center
Stanley B. Kaye: Section of Medicine, Institute of Cancer Research
Linda E. Kelemen: Alberta Health Services-Cancer Care, Calgary, Alberta, University of Calgary
Lambertus A. Kiemeney: Biostatistics and HTA, Radboud University Medical Centre
Fumitaka Kikkawa: Nagoya University Graduate School of Medicine
Gottfried E. Konecny: David Geffen School of Medicine, University of California at Los Angeles
Camilla Krakstad: Haukeland University Hospital
Susanne Krüger Kjaer: The Juliane Marie Centre
Jolanta Kupryjanczyk: The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology
Diether Lambrechts: Vesalius Research Center, VIB
Sandrina Lambrechts: University Hospitals Leuven
Johnathan M. Lancaster: Moffitt Cancer Center
Nhu D. Le: Cancer Control Research, BC Cancer Agency
Arto Leminen: University of Helsinki and Helsinki University Central Hospital
Douglas A. Levine: Gynecology Service, Memorial Sloan-Kettering Cancer Center
Dong Liang: College of Pharmacy and Health Sciences, Texas Southern University
Boon Kiong Lim: Affiliated to UM Cancer Research Institute, Faculty of Medicine, University Malaya
Jie Lin: The University of Texas MD Anderson Cancer Center
Jolanta Lissowska: The Maria Sklodowska-Curie Memorial Cancer Center
Karen H. Lu: The University of Texas MD Anderson Cancer Center
Jan Lubiński: International Hereditary Cancer Center, Pomeranian Medical University
Galina Lurie: Cancer Epidemiology Program, University of Hawaii Cancer Center
Leon F.A.G Massuger: Radboud University Medical Centre
Keitaro Matsuo: Aichi Cancer Center Research Institute
Valerie McGuire: Stanford University School of Medicine
John R. McLaughlin: Dalla Lana School of Public Health, Faculty of Medicine, University of Toronto
Usha Menon: Gynaecological Cancer Research Centre, Women’s Cancer, Institute for Women's Health, University College London
Francesmary Modugno: Womens Cancer Research Program, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute
Kirsten B. Moysich: Roswell Park Cancer Institute
Toru Nakanishi: Aichi Cancer Center Central Hospital
Steven A. Narod: Women’s College Research Institute, University of Toronto
Lotte Nedergaard: Rigshospitalet, University of Copenhagen
Roberta B. Ness: The University of Texas School of Public Health
Heli Nevanlinna: Helsinki University Central Hospital
Stefan Nickels: German Cancer Research Center
Houtan Noushmehr: Microbiology and Preventive Medicine, University of Southern California, Norris Comprehensive Cancer Center
Kunle Odunsi: Roswell Park Cancer Institute
Sara H. Olson: Memorial Sloan-Kettering Cancer Center
Irene Orlow: Memorial Sloan-Kettering Cancer Center
James Paul: The Beatson West of Scotland Cancer Centre
Celeste L. Pearce: Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles
Tanja Pejovic: Oregon Health and Science University
Liisa M. Pelttari: Helsinki University Central Hospital
Malcolm C. Pike: Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles
Elizabeth M. Poole: Harvard Medical School and Brigham and Women’s Hospital
Paola Raska: Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine
Stefan P. Renner: University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center
Harvey A. Risch: Yale University School of Public Health and School of Medicine
Lorna Rodriguez-Rodriguez: The Cancer Institute of New Jersey, Robert Wood Johnson Medical School
Mary Anne Rossing: Program in Epidemiology, Fred Hutchinson Cancer Research Center
Anja Rudolph: German Cancer Research Center
Ingo B. Runnebaum: Jena University Hospital
Iwona K. Rzepecka: The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology
Helga B. Salvesen: Haukeland University Hospital
Ira Schwaab: Institut für Humangenetik Wiesbaden
Gianluca Severi: Cancer Epidemiology Centre, The Cancer Council Victoria
Viji Shridhar: Mayo Clinic
Xiao-Ou Shu: Vanderbilt Epidemiology Center and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine
Yurii B. Shvetsov: Cancer Epidemiology Program, University of Hawaii Cancer Center
Weiva Sieh: Stanford University School of Medicine
Honglin Song: University of Cambridge
Melissa C. Southey: Genetic Epidemiology Laboratory, The University of Melbourne
Beata Spiewankiewicz: The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology
Daniel Stram: Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles
Rebecca Sutphen: Pediatrics Epidemiology Center, College of Medicine, University of South Florida
Soo-Hwang Teo: Cancer Research Initiatives Foundation, Sime Darby Medical Centre
Kathryn L. Terry: Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School
Daniel C. Tessier: McGill University and Génome Québec Innovation Centre
Pamela J. Thompson: Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center
Shelley S. Tworoger: Harvard Medical School and Brigham and Women’s Hospital
Anne M. van Altena: Radboud University Medical Centre
Ignace Vergote: University Hospitals Leuven
Robert A. Vierkant: Mayo Clinic
Daniel Vincent: McGill University and Génome Québec Innovation Centre
Allison F. Vitonis: Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School
Shan Wang-Gohrke: University of Ulm
Rachel Palmieri Weber: Duke University Medical Center
Nicolas Wentzensen: National Cancer Institute
Alice S. Whittemore: Stanford University School of Medicine
Elisabeth Wik: Haukeland University Hospital
Lynne R. Wilkens: Cancer Epidemiology Program, University of Hawaii Cancer Center
Boris Winterhoff: Mayo Clinic
Yin Ling Woo: Affiliated to UM Cancer Research Institute, Faculty of Medicine, University Malaya
Anna H. Wu: Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles
Yong-Bing Xiang: Shanghai Cancer Institute
Hannah P. Yang: National Cancer Institute
Wei Zheng: Vanderbilt Epidemiology Center and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine
Argyrios Ziogas: Center for Cancer Genetics Research and Prevention, School of Medicine, University of California Irvine
Famida Zulkifli: Cancer Research Initiatives Foundation, Sime Darby Medical Centre
Catherine M. Phelan: Moffitt Cancer Center, Tampa
Edwin Iversen: Duke University
Joellen M. Schildkraut: Duke University Medical Center
Andrew Berchuck: Duke Cancer Institute
Brooke L. Fridley: University of Kansas Medical Center
Ellen L. Goode: Mayo Clinic College of Medicine
Paul D.P. Pharoah: Centre for Cancer Genetic Epidemiology, University of Cambridge
Alvaro N.A. Monteiro: Moffitt Cancer Center, Tampa
Thomas A. Sellers: Moffitt Cancer Center, Tampa
Simon A. Gayther: Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles

Nature Communications, 2013, vol. 4, issue 1, 1-12

Abstract: Abstract Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3′ untranslated region at putative microRNA (miRNA)-binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA-related single-nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene–environment Study. We identify several miRSNPs associated with invasive serous EOC risk (odds ratio=1.12, P=10−8) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10−10). Variation at 17q21.31 is associated with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes.

Date: 2013
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DOI: 10.1038/ncomms2613

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