Alice W Lee1, Jonathan P Tyrer2, Jennifer A Doherty3, Douglas A Stram1, Jolanta Kupryjanczyk4, Agnieszka Dansonka-Mieszkowska4, Joanna Plisiecka-Halasa4, Beata Spiewankiewicz5, Emily J Myers1, Georgia Chenevix-Trench6, Peter A Fasching7, Matthias W Beckmann8, Arif B Ekici9, Alexander Hein8, Ignace Vergote10, Els Van Nieuwenhuysen10, Diether Lambrechts11, Kristine G Wicklund12, Ursula Eilber13, Shan Wang-Gohrke14, Jenny Chang-Claude13, Anja Rudolph13, Lara Sucheston-Campbell15, Kunle Odunsi16, Kirsten B Moysich15, Yurii B Shvetsov17, Pamela J Thompson18, Marc T Goodman18, Lynne R Wilkens17, Thilo Dörk19, Peter Hillemanns20, Matthias Dürst21, Ingo B Runnebaum21, Natalia Bogdanova19, Liisa M Pelttari22, Heli Nevanlinna22, Arto Leminen22, Robert P Edwards23, Joseph L Kelley24, Philipp Harter25, Ira Schwaab26, Florian Heitz25, Andreas du Bois25, Sandra Orsulic27, Jenny Lester27, Christine Walsh27, Beth Y Karlan27, Estrid Hogdall28, Susanne K Kjaer29, Allan Jensen30, Robert A Vierkant31, Julie M Cunningham32, Ellen L Goode31, Brooke L Fridley33, Melissa C Southey34, Graham G Giles35, Fiona Bruinsma36, Xifeng Wu37, Michelle A T Hildebrandt37, Karen Lu38, Dong Liang39, Maria Bisogna40, Douglas A Levine40, Rachel Palmieri Weber41, Joellen M Schildkraut42, Edwin S Iversen43, Andrew Berchuck44, Kathryn L Terry45, Daniel W Cramer45, Shelley S Tworoger46, Elizabeth M Poole46, Sara H Olson47, Irene Orlow47, Elisa V Bandera48, Line Bjorge49, Ingvild L Tangen49, Helga B Salvesen49, Camilla Krakstad49, Leon F A G Massuger50, Lambertus A Kiemeney51, Katja K H Aben52, Anne M van Altena50, Yukie Bean53, Tanja Pejovic53, Melissa Kellar53, Nhu D Le54, Linda S Cook55, Linda E Kelemen56, Angela Brooks-Wilson57, Jan Lubinski58, Jacek Gronwald58, Cezary Cybulski58, Anna Jakubowska58, Nicolas Wentzensen59, Louise A Brinton59, Jolanta Lissowska60, Hannah Yang59, Lotte Nedergaard61, Lene Lundvall62, Claus Hogdall62, Honglin Song2, Ian G Campbell63, Diana Eccles64, Rosalind Glasspool65, Nadeem Siddiqui66, Karen Carty65, James Paul65, Iain A McNeish67, Weiva Sieh68, Valerie McGuire68, Joseph H Rothstein68, Alice S Whittemore68, John R McLaughlin69, Harvey A Risch70, Catherine M Phelan71, Hoda Anton-Culver72, Argyrios Ziogas73, Usha Menon74, Susan J Ramus1, Aleksandra Gentry-Maharaj74, Patricia Harrington75, Malcolm C Pike76, Francesmary Modugno77, Mary Anne Rossing78, Roberta B Ness79, Paul D P Pharoah80, Daniel O Stram1, Anna H Wu1, Celeste Leigh Pearce81. 1. Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA. 2. Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK. 3. Department of Epidemiology, The Geisel School of Medicine at Dartmouth, Lebanon, NH, USA. 4. Department of Pathology, Institute of Oncology, Warsaw, Poland. 5. Department of Gynecologic Oncology, Institute of Oncology, Warsaw, Poland. 6. Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. 7. University of California at Los Angeles, David Geffen School of Medicine, Department of Medicine, Division of Hematology and Oncology, Los Angeles, CA, USA; University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Universitaetsstrasse 21-23, 91054 Erlangen, Germany. 8. University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Universitaetsstrasse 21-23, 91054 Erlangen, Germany. 9. University Hospital Erlangen, Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany. 10. Division of Gynecological Oncology, Department of Oncology, University Hospitals Leuven, Belgium. 11. Vesalius Research Center, VIB, Leuven, Belgium; Laboratory for Translational Genetics, Vesalius Research Center, VIB and KU Leuven, Belgium. 12. Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. 13. German Cancer Research Center (DKFZ), Division of Cancer Epidemiology, Heidelberg, Germany. 14. Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany. 15. Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA. 16. Department of Gynecological Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA. 17. Cancer Epidemiology Program, University of Hawaii Cancer Center, HI, USA. 18. Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Community and Population Health Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA. 19. Gynaecology Research Unit, Hannover Medical School, Hannover, Germany. 20. Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany. 21. Department of Gynecology, Jena University Hospital - Friedrich Schiller University, Jena, Germany. 22. Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, HUS, Finland. 23. Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Ovarian Cancer Center of Excellence, University of Pittsburgh, Pittsburgh, PA, USA. 24. Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. 25. Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, Essen, Germany; Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany. 26. Institut für Humangenetik Wiesbaden, Wiesbaden, Germany. 27. Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. 28. Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark; Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark. 29. Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark; Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 30. Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark. 31. Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA. 32. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. 33. Biostatistics and Informatics Shared Resource, University of Kansas Medical Center, Kansas City, KS, USA. 34. Department of Pathology, University of Melbourne, Parkville, VIC Australia. 35. Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia. 36. Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC, Australia. 37. Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 38. Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 39. College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, USA. 40. Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 41. Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA. 42. Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA; Cancer Control and Population Sciences, Duke Cancer Institute, Durham, NC, USA. 43. Department of Statistical Science, Duke University, Durham, NC, USA. 44. Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA. 45. Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA. 46. Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. 47. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 48. Cancer Prevention and Control, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA. 49. Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway; Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway. 50. Department of Gynaecology, Radboud University Medical Centre, Nijmegen, The Netherlands. 51. Department for Health Evidence and Department of Urology, Radboud University Medical Centre, Nijmegen, The Netherlands. 52. Department for Health Evidence, Radboud University Medical Centre, Nijmegen, The Netherlands; Comprehensive Cancer Center The Netherlands, Utrecht, The Netherlands. 53. Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR, USA; Knight Cancer Institute, Portland, OR, USA. 54. Cancer Control Research, BC Cancer Agency, Vancouver, BC, Canada. 55. Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA. 56. Alberta Health Services-Cancer Care, Department of Population Health Research, Calgary, AB, Canada; Departments of Medical Genetics and Oncology, University of Calgary, Calgary, AB, Canada. 57. Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada; Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC Canada. 58. Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland. 59. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA. 60. Department of Cancer Epidemiology and Prevention, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. 61. Deptartment of Pathology, Rigshospitalet, University of Copenhagen, Denmark. 62. Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 63. Department of Pathology, University of Melbourne, Parkville, VIC Australia; Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia. 64. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK. 65. Cancer Research UK Clinical Trials Unit, Glasgow, The Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, UK. 66. Department of Gynaecological Oncology, Glasgow Royal Infirmary, Glasgow, UK. 67. Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Beatson Institute for Cancer Research, Glasgow, UK. 68. Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, CA, USA. 69. Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada. 70. Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA. 71. Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA. 72. Department of Epidemiology, Genetic Epidemiology Research Institute, School of Medicine, University of California Irvine, Irvine, CA, USA. 73. Department of Epidemiology, University of California Irvine, Irvine, CA, USA. 74. Women's Cancer, Institute for Women's Health, University College London, London, UK. 75. Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK. 76. Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 77. Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Women's Cancer Research Program, Magee-Women's Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA; Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. 78. Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA. 79. The University of Texas School of Public Health, Houston, TX, USA. 80. Department of Oncology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK. 81. Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA; Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA. Electronic address: lpearce@umich.edu.
Abstract
OBJECTIVE: Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted. METHODS: Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2185 SNPs from 11 gonadotropin signaling pathway genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations. RESULTS: We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some suggestion of gene-level associations for four gonadotropin signaling pathway genes: INHBB (p=0.045, mucinous), LHCGR (p=0.046, high-grade serous), GNRH (p=0.041, high-grade serous), and FSHB (p=0.036, overall invasive). There was also suggestive evidence for INHA (p=0.060, overall invasive). CONCLUSIONS: Ovarian cancer studies have limited sample numbers, thus fewer genome-wide susceptibility alleles, with only modest associations, have been identified relative to breast and prostate cancers. We have evaluated the majority of ovarian cancer studies with biological samples, to our knowledge, leaving no opportunity for replication. Using both our understanding of biology and powerful gene-level tests, we have identified four putative ovarian cancer loci near INHBB, LHCGR, GNRH, and FSHB that warrant a second look if larger sample sizes and denser genotype chips become available.
OBJECTIVE: Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted. METHODS: Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2185 SNPs from 11 gonadotropin signaling pathway genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations. RESULTS: We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some suggestion of gene-level associations for four gonadotropin signaling pathway genes: INHBB (p=0.045, mucinous), LHCGR (p=0.046, high-grade serous), GNRH (p=0.041, high-grade serous), and FSHB (p=0.036, overall invasive). There was also suggestive evidence for INHA (p=0.060, overall invasive). CONCLUSIONS: Ovarian cancer studies have limited sample numbers, thus fewer genome-wide susceptibility alleles, with only modest associations, have been identified relative to breast and prostate cancers. We have evaluated the majority of ovarian cancer studies with biological samples, to our knowledge, leaving no opportunity for replication. Using both our understanding of biology and powerful gene-level tests, we have identified four putative ovarian cancer loci near INHBB, LHCGR, GNRH, and FSHB that warrant a second look if larger sample sizes and denser genotype chips become available.
Authors: Ellen L Goode; Georgia Chenevix-Trench; Honglin Song; Susan J Ramus; Maria Notaridou; Kate Lawrenson; Martin Widschwendter; Robert A Vierkant; Melissa C Larson; Susanne K Kjaer; Michael J Birrer; Andrew Berchuck; Joellen Schildkraut; Ian Tomlinson; Lambertus A Kiemeney; Linda S Cook; Jacek Gronwald; Montserrat Garcia-Closas; Martin E Gore; Ian Campbell; Alice S Whittemore; Rebecca Sutphen; Catherine Phelan; Hoda Anton-Culver; Celeste Leigh Pearce; Diether Lambrechts; Mary Anne Rossing; Jenny Chang-Claude; Kirsten B Moysich; Marc T Goodman; Thilo Dörk; Heli Nevanlinna; Roberta B Ness; Thorunn Rafnar; Claus Hogdall; Estrid Hogdall; Brooke L Fridley; Julie M Cunningham; Weiva Sieh; Valerie McGuire; Andrew K Godwin; Daniel W Cramer; Dena Hernandez; Douglas Levine; Karen Lu; Edwin S Iversen; Rachel T Palmieri; Richard Houlston; Anne M van Altena; Katja K H Aben; Leon F A G Massuger; Angela Brooks-Wilson; Linda E Kelemen; Nhu D Le; Anna Jakubowska; Jan Lubinski; Krzysztof Medrek; Anne Stafford; Douglas F Easton; Jonathan Tyrer; Kelly L Bolton; Patricia Harrington; Diana Eccles; Ann Chen; Ashley N Molina; Barbara N Davila; Hector Arango; Ya-Yu Tsai; Zhihua Chen; Harvey A Risch; John McLaughlin; Steven A Narod; Argyrios Ziogas; Wendy Brewster; Aleksandra Gentry-Maharaj; Usha Menon; Anna H Wu; Daniel O Stram; Malcolm C Pike; Jonathan Beesley; Penelope M Webb; Xiaoqing Chen; Arif B Ekici; Falk C Thiel; Matthias W Beckmann; Hannah Yang; Nicolas Wentzensen; Jolanta Lissowska; Peter A Fasching; Evelyn Despierre; Frederic Amant; Ignace Vergote; Jennifer Doherty; Rebecca Hein; Shan Wang-Gohrke; Galina Lurie; Michael E Carney; Pamela J Thompson; Ingo Runnebaum; Peter Hillemanns; Matthias Dürst; Natalia Antonenkova; Natalia Bogdanova; Arto Leminen; Ralf Butzow; Tuomas Heikkinen; Kari Stefansson; Patrick Sulem; Sören Besenbacher; Thomas A Sellers; Simon A Gayther; Paul D P Pharoah Journal: Nat Genet Date: 2010-09-19 Impact factor: 38.330
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Authors: Shalaka S Hampras; Lara E Sucheston-Campbell; Rikki Cannioto; Jenny Chang-Claude; Francesmary Modugno; Thilo Dörk; Peter Hillemanns; Leah Preus; Keith L Knutson; Paul K Wallace; Chi-Chen Hong; Grace Friel; Warren Davis; Mary Nesline; Celeste L Pearce; Linda E Kelemen; Marc T Goodman; Elisa V Bandera; Kathryn L Terry; Nils Schoof; Kevin H Eng; Alyssa Clay; Prashant K Singh; Janine M Joseph; Katja K H Aben; Hoda Anton-Culver; Natalia Antonenkova; Helen Baker; Yukie Bean; Matthias W Beckmann; Maria Bisogna; Line Bjorge; Natalia Bogdanova; Louise A Brinton; Angela Brooks-Wilson; Fiona Bruinsma; Ralf Butzow; Ian G Campbell; Karen Carty; Linda S Cook; Daniel W Cramer; Cezary Cybulski; Agnieszka Dansonka-Mieszkowska; Joe Dennis; Evelyn Despierre; Ed Dicks; Jennifer A Doherty; Andreas du Bois; Matthias Dürst; Doug Easton; Diana Eccles; Robert P Edwards; Arif B Ekici; Peter A Fasching; Brooke L Fridley; Yu-Tang Gao; Aleksandra Gentry-Maharaj; Graham G Giles; Rosalind Glasspool; Jacek Gronwald; Patricia Harrington; Philipp Harter; Hanis Nazihah Hasmad; Alexander Hein; Florian Heitz; Michelle A T Hildebrandt; Claus Hogdall; Estrid Hogdall; Satoyo Hosono; Edwin S Iversen; Anna Jakubowska; Allan Jensen; Bu-Tian Ji; Beth Y Karlan; Melissa Kellar; Joseph L Kelley; Lambertus A Kiemeney; Rüdiger Klapdor; Nonna Kolomeyevskaya; Camilla Krakstad; Susanne K Kjaer; Bridget Kruszka; Jolanta Kupryjanczyk; Diether Lambrechts; Sandrina Lambrechts; Nhu D Le; Alice W Lee; Shashikant Lele; Arto Leminen; Jenny Lester; Douglas A Levine; Dong Liang; Jolanta Lissowska; Song Liu; Karen Lu; Jan Lubinski; Lene Lundvall; Leon F A G Massuger; Keitaro Matsuo; Valeria McGuire; John R McLaughlin; Ian McNeish; Usha Menon; Joanna Moes-Sosnowska; Steven A Narod; Lotte Nedergaard; Heli Nevanlinna; Stefan Nickels; Sara H Olson; Irene Orlow; Rachel Palmieri Weber; James Paul; Tanja Pejovic; Liisa M Pelttari; Barbara Perkins; Jenny Permuth-Wey; Malcolm C Pike; Joanna Plisiecka-Halasa; Elizabeth M Poole; Harvey A Risch; Mary Anne Rossing; Joseph H Rothstein; Anja Rudolph; Ingo B Runnebaum; Iwona K Rzepecka; Helga B Salvesen; Eva Schernhammer; Kristina Schmitt; Ira Schwaab; Xiao-Ou Shu; Yurii B Shvetsov; Nadeem Siddiqui; Weiva Sieh; Honglin Song; Melissa C Southey; Ingvild L Tangen; Soo-Hwang Teo; Pamela J Thompson; Agnieszka Timorek; Ya-Yu Tsai; Shelley S Tworoger; Jonathan Tyrer; Anna M van Altena; Ignace Vergote; Robert A Vierkant; Christine Walsh; Shan Wang-Gohrke; Nicolas Wentzensen; Alice S Whittemore; Kristine G Wicklund; Lynne R Wilkens; Anna H Wu; Xifeng Wu; Yin-Ling Woo; Hannah Yang; Wei Zheng; Argyrios Ziogas; Simon A Gayther; Susan J Ramus; Thomas A Sellers; Joellen M Schildkraut; Catherine M Phelan; Andrew Berchuck; Georgia Chenevix-Trench; Julie M Cunningham; Paul P Pharoah; Roberta B Ness; Kunle Odunsi; Ellen L Goode; Kirsten B Moysich Journal: Oncotarget Date: 2016-10-25