Assessing the genetic architecture of epithelial ovarian cancer histological subtypes View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2016-07

AUTHORS

Gabriel Cuellar-Partida, Yi Lu, Suzanne C. Dixon, Australian Ovarian Cancer Study, Peter A. Fasching, Alexander Hein, Stefanie Burghaus, Matthias W. Beckmann, Diether Lambrechts, Els Van Nieuwenhuysen, Ignace Vergote, Adriaan Vanderstichele, Jennifer Anne Doherty, Mary Anne Rossing, Jenny Chang-Claude, Anja Rudolph, Shan Wang-Gohrke, Marc T. Goodman, Natalia Bogdanova, Thilo Dörk, Matthias Dürst, Peter Hillemanns, Ingo B. Runnebaum, Natalia Antonenkova, Ralf Butzow, Arto Leminen, Heli Nevanlinna, Liisa M. Pelttari, Robert P. Edwards, Joseph L. Kelley, Francesmary Modugno, Kirsten B. Moysich, Roberta B. Ness, Rikki Cannioto, Estrid Høgdall, Claus Høgdall, Allan Jensen, Graham G. Giles, Fiona Bruinsma, Susanne K. Kjaer, Michelle A. T. Hildebrandt, Dong Liang, Karen H. Lu, Xifeng Wu, Maria Bisogna, Fanny Dao, Douglas A. Levine, Daniel W. Cramer, Kathryn L. Terry, Shelley S. Tworoger, Meir Stampfer, Stacey Missmer, Line Bjorge, Helga B. Salvesen, Reidun K. Kopperud, Katharina Bischof, Katja K. H. Aben, Lambertus A. Kiemeney, Leon F. A. G. Massuger, Angela Brooks-Wilson, Sara H. Olson, Valerie McGuire, Joseph H. Rothstein, Weiva Sieh, Alice S. Whittemore, Linda S. Cook, Nhu D. Le, C. Blake Gilks, Jacek Gronwald, Anna Jakubowska, Jan Lubiński, Tomasz Kluz, Honglin Song, Jonathan P. Tyrer, Nicolas Wentzensen, Louise Brinton, Britton Trabert, Jolanta Lissowska, John R. McLaughlin, Steven A. Narod, Catherine Phelan, Hoda Anton-Culver, Argyrios Ziogas, Diana Eccles, Ian Campbell, Simon A. Gayther, Aleksandra Gentry-Maharaj, Usha Menon, Susan J. Ramus, Anna H. Wu, Agnieszka Dansonka-Mieszkowska, Jolanta Kupryjanczyk, Agnieszka Timorek, Lukasz Szafron, Julie M. Cunningham, Brooke L. Fridley, Stacey J. Winham, Elisa V. Bandera, Elizabeth M. Poole, Terry K. Morgan, Ellen L. Goode, Joellen M. Schildkraut, Celeste L. Pearce, Andrew Berchuck, Paul D. P. Pharoah, Penelope M. Webb, Georgia Chenevix-Trench, Harvey A. Risch, Stuart MacGregor

ABSTRACT

Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease ([Formula: see text] = 8.8 ± 1.1 %), endometrioid ([Formula: see text] = 3.2 ± 1.6 %), clear cell ([Formula: see text] = 6.7 ± 3.3 %) and all EOC ([Formula: see text] = 5.6 ± 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach. More... »

PAGES

741-756

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  • Journal

    TITLE

    Human Genetics

    ISSUE

    7

    VOLUME

    135

    Author Affiliations

  • University of Queensland
  • QIMR Berghofer Medical Research Institute
  • Peter MacCallum Cancer Centre
  • University of California Los Angeles
  • Flanders Institute for Biotechnology
  • Universitaire Ziekenhuizen Leuven
  • Dartmouth College
  • Fred Hutchinson Cancer Research Center
  • University Cancer Center Hamburg
  • German Cancer Research Center
  • University of Ulm
  • Cedars-Sinai Medical Center
  • Hannover Medical School
  • Friedrich Schiller University Jena
  • N.N. Alexandrov National Cancer Centre
  • Helsinki University Central Hospital
  • University of Pittsburgh Cancer Institute
  • University of Pittsburgh
  • Roswell Park Cancer Institute
  • The University of Texas Health Science Center at Houston
  • University of Copenhagen
  • Danish Cancer Society
  • Cancer Council Victoria
  • The University of Texas MD Anderson Cancer Center
  • Texas Southern University
  • Memorial Sloan Kettering Cancer Center
  • Brigham and Women's Hospital
  • Harvard University
  • University of Bergen
  • Netherlands Comprehensive Cancer Organisation
  • Radboud University Nijmegen Medical Centre
  • Simon Fraser University
  • Stanford University
  • University of New Mexico
  • BC Cancer Agency
  • University of British Columbia
  • Pomeranian Medical University
  • Rzeszów University
  • University of Cambridge
  • National Cancer Institute
  • Centrum Onkologii Instytut
  • Public Health Ontario
  • University of Toronto
  • Moffitt Cancer Center
  • University of California, Irvine
  • University of Southampton
  • University of Southern California
  • University College London
  • Mayo Clinic
  • University of Kansas
  • Rutgers University
  • Oregon Health & Science University
  • University of Virginia
  • University of Michigan–Ann Arbor
  • Duke University
  • Yale University
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1007/s00439-016-1663-9

    DOI

    http://dx.doi.org/10.1007/s00439-016-1663-9

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1037515608

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/27075448


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