Oncotarget

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A targeted genetic association study of epithelial ovarian cancer susceptibility

Madalene Earp, Stacey J. Winham, Nicholas Larson, Jennifer B. Permuth, Hugues Sicotte, Jeremy Chien, Hoda Anton-Culver, Elisa V. Bandera, Andrew Berchuck, Linda S. Cook, Daniel Cramer, Jennifer A. Doherty, Marc T. Goodman, Douglas A. Levine, Alvaro N.A. Monteiro, Roberta B. Ness, Celeste L. Pearce, Mary Anne Rossing, Shelley S. Tworoger, Nicolas Wentzensen, Maria Bisogna, Louise Brinton, Angela Brooks-Wilson, Michael E. Carney, Julie M. Cunningham, Robert P. Edwards, Zachary C. Fogarty, Edwin S. Iversen, Peter Kraft, Melissa C. Larson, Nhu D. Le, Hui-Yi Lin, Jolanta Lissowska, Francesmary Modugno, Kirsten B. Moysich, Sara H. Olson, Malcolm C. Pike, Elizabeth M. Poole, David N. Rider, Kathryn L. Terry, Pamela J. Thompson, David van den Berg, Robert A. Vierkant, Allison F. Vitonis, Lynne R. Wilkens, Anna H. Wu, Hannah P. Yang, Argyrios Ziogas, Catherine M. Phelan, Joellen M. Schildkraut, Yian Ann Chen, Thomas A. Sellers, Brooke L. Fridley and Ellen L. Goode _

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Oncotarget. 2016; 7:7381-7389. https://doi.org/10.18632/oncotarget.7121

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Abstract

Madalene Earp1, Stacey J. Winham2, Nicholas Larson2, Jennifer B. Permuth3, Hugues Sicotte2, Jeremy Chien4, Hoda Anton-Culver5, Elisa V. Bandera6, Andrew Berchuck7, Linda S. Cook8, Daniel Cramer9,10, Jennifer A. Doherty11, Marc T. Goodman12, Douglas A. Levine13, Alvaro N.A. Monteiro3, Roberta B. Ness14, Celeste L. Pearce15, Mary Anne Rossing16,17, Shelley S. Tworoger10,18, Nicolas Wentzensen19, Maria Bisogna13, Louise Brinton19, Angela Brooks-Wilson20,21, Michael E. Carney22, Julie M. Cunningham23, Robert P. Edwards24, Zachary C. Fogarty2, Edwin S. Iversen25, Peter Kraft26, Melissa C. Larson2, Nhu D. Le27, Hui-Yi Lin3, Jolanta Lissowska28, Francesmary Modugno24,29,30, Kirsten B. Moysich31, Sara H. Olson32, Malcolm C. Pike15,31, Elizabeth M. Poole18, David N. Rider2, Kathryn L. Terry9,10, Pamela J. Thompson12, David van den Berg15, Robert A. Vierkant2, Allison F. Vitonis9, Lynne R. Wilkens33, Anna H. Wu15, Hannah P. Yang19, Argyrios Ziogas34, Catherine M. Phelan3, Joellen M. Schildkraut35,36, Yian Ann Chen3, Thomas A. Sellers3, Brooke L. Fridley37 and Ellen L. Goode1

1 Department of Health Sciences Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA

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

3 Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

4 Department of Cancer Biology, University of Kansas Cancer Center, Kansas City, KS, USA

5 Department of Epidemiology, University of California Irvine, Irvine, CA, USA

6 Rutgers Cancer Institute of New Jersey and Robert Wood Johnson Medical School, New Brunswick, NJ, USA

7 Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA

8 Division of Epidemiology and Biostatistics, University of New Mexico, Albuquerque, NM, USA

9 Obstetrics and Gynecology Epidemiology Center, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

10 Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA

11 Section of Biostatistics and Epidemiology, The Geisel School of Medicine at Dartmouth, Lebanon, NH, USA

12 Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA

13 Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

14 The University of Texas School of Public Health, Houston, TX, USA

15 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

16 Department of Epidemiology, University of Washington, Seattle, WA, USA

17 Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

18 Channing Division of Network Medicine, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA

19 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA

20 Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada

21 Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada

22 Clinical and Translational Research Program, University of Hawaii Cancer Center, Honolulu, HI, USA

23 Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic, Rochester, MN, USA

24 Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Gynecologic Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

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

26 Departments of Epidemiology and Biostatistics, Harvard School of Public Health, Boston, MA, USA

27 Cancer Control Research, BC Cancer Agency, Vancouver, BC, Canada

28 Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center & Institute of Oncology, Warsaw, Poland

29 Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA

30 Cancer Research Program, Magee-Women’s Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

31 Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, US

32 Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

33 Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA

34 Department of Epidemiology, Center for Cancer Genetics Research and Prevention, School of Medicine, University of California Irvine, Irvine, CA, USA

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

36 Cancer Prevention, Detection and Control Research Program, Duke Cancer Institute, Durham, NC, USA

37 Kansas IDeA Network of Biomedical Research Excellence Bioinformatics Core, University of Kansas Cancer Center, Kansas City, KS, USA

Correspondence to:

Ellen L. Goode, email:

Keywords: ovarian cancer, high-grade serous carcinoma, genetic association, susceptibility loci, NF-κB

Received: October 16, 2015 Accepted: January 24, 2016 Published: February 01, 2016

Abstract

Background: Genome-wide association studies have identified several common susceptibility alleles for epithelial ovarian cancer (EOC). To further understand EOC susceptibility, we examined previously ungenotyped candidate variants, including uncommon variants and those residing within known susceptibility loci.

Results: At nine of eleven previously published EOC susceptibility regions (2q31, 3q25, 5p15, 8q21, 8q24, 10p12, 17q12, 17q21.31, and 19p13), novel variants were identified that were more strongly associated with risk than previously reported variants. Beyond known susceptibility regions, no variants were found to be associated with EOC risk at genome-wide statistical significance (p <5x10-8), nor were any significant after Bonferroni correction for 17,000 variants (p< 3x10-6).

Methods: A customized genotyping array was used to assess over 17,000 variants in coding, non-coding, regulatory, and known susceptibility regions in 4,973 EOC cases and 5,640 controls from 13 independent studies. Susceptibility for EOC overall and for select histotypes was evaluated using logistic regression adjusted for age, study site, and population substructure.

Conclusion: Given the novel variants identified within the 2q31, 3q25, 5p15, 8q21, 8q24, 10p12, 17q12, 17q21.31, and 19p13 regions, larger follow-up genotyping studies, using imputation where necessary, are needed for fine-mapping and confirmation of low frequency variants that fall below statistical significance.


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