Assessing the genetic architecture of epithelial ovarian cancer histological subtypes

Cuellar-Partida G, Lu Y, Dixon SC, Fasching PA, Hein A, Burghaus S, Beckmann M, Lambrechts D, Van Nieuwenhuysen E, Vergote I, Vanderstichele A, Doherty JA, Rossing MA, Chang-Claude J, Rudolph A, Wang-Gohrke S, Goodman MT, Bogdanova N, Doerk T, Duerst M, Hillemanns P, Runnebaum IB, Antonenkova N, Butzow R, Leminen A, Nevanlinna H, Pelttari LM, Edwards RP, Kelley JL, Modugno F, Moysich KB, Ness RB, Cannioto R, Hogdall E, Hogdall C, Jensen A, Giles GG, Bruinsma F, Kjaer SK, Hildebrandt MAT, Liang D, Lu KH, Wu X, Bisogna M, Dao F, Levine DA, Cramer DW, Terry KL, Tworoger SS, Stampfer M, Missmer S, Bjorge L, Salvesen HB, Kopperud RK, Bischof K, Aben KKH, Kiemeney LA, Massuger LFAG, Brooks-Wilson A, Olson SH, Mcguire V, Rothstein JH, Sieh W, Whittemore AS, Cook LS, Le ND, Gilks CB, Gronwald J, Jakubowska A, Lubinski J, Kluz T, Song H, Tyrer JP, Wentzensen N, Brinton L, Trabert B, Lissowska J, Mclaughlin JR, Narod SA, Phelan C, Anton-Culver H, Ziogas A, Eccles D, Campbell I, Gayther SA, Gentry-Maharaj A, Menon U, Ramus SJ, Wu AH, Dansonka-Mieszkowska A, Kupryjanczyk J, Timorek A, Szafron L, Cunningham JM, Fridley BL, Winham SJ, Bandera EV, Poole EM, Morgan TK, Goode EL, Schildkraut JM, Pearce CL, Berchuck A, Pharoah PDP, Webb PM, Chenevix-Trench G, Risch HA, Macgregor S (2016)


Publication Type: Journal article

Publication year: 2016

Journal

Book Volume: 135

Pages Range: 741-56

Journal Issue: 7

DOI: 10.1007/s00439-016-1663-9

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.

Authors with CRIS profile

Involved external institutions

Helsingin yliopisto / University of Helsinki FI Finland (FI) Helsinki University Central Hospital (HUCH) / Helsingin seudun yliopistollinen keskussairaala (HYKS) FI Finland (FI) University of Pittsburgh US United States (USA) (US) Roswell Park Cancer Institute US United States (USA) (US) University of Texas MD Anderson Cancer Center US United States (USA) (US) Danish Cancer Society Research Center DK Denmark (DK) University of Copenhagen DK Denmark (DK) Monash University AU Australia (AU) Cancer Council Victoria AU Australia (AU) Texas Southern University (TSU) US United States (USA) (US) Memorial Sloan Kettering Cancer Center US United States (USA) (US) Brigham and Women's Hospital (BWH) US United States (USA) (US) Harvard University US United States (USA) (US) Haukeland University Hospital / Haukeland universitetssykehus NO Norway (NO) Radboud University Nijmegen NL Netherlands (NL) British Columbia Cancer Agency CA Canada (CA) University of British Columbia CA Canada (CA) Wrocław Medical University / Uniwersytet Medyczny we Wrocławiu PL Poland (PL) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) AU Australia (AU) University of California Los Angeles (UCLA) US United States (USA) (US) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven BE Belgium (BE) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven BE Belgium (BE) Dartmouth College US United States (USA) (US) University of Washington US United States (USA) (US) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE) Universität Ulm DE Germany (DE) Cedars-Sinai Medical Center US United States (USA) (US) Medizinische Hochschule Hannover (MHH) / Hannover Medical School DE Germany (DE) Friedrich-Schiller-Universität Jena DE Germany (DE) N.N. Alexandrov National Cancer Centre of Belarus for Oncology and Medical Radiology BY Belarus (BY) Stanford University US United States (USA) (US) University of New Mexico (UNM) / Universidad de Nuevo México US United States (USA) (US) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) PL Poland (PL) Uniwersytet Rzeszowski PL Poland (PL) University of Cambridge GB United Kingdom (GB) National Cancer Institute (NCI) US United States (USA) (US) Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie PL Poland (PL) Public Health Ontario CA Canada (CA) University of Toronto CA Canada (CA) H. Lee Moffitt Cancer Center & Research Institute US United States (USA) (US) University of California Irvine US United States (USA) (US) University of Southampton GB United Kingdom (GB) Peter MacCallum Cancer Centre AU Australia (AU) University of Southern California (USC) US United States (USA) (US) University College London (UCL) GB United Kingdom (GB) Mayo Clinic US United States (USA) (US) University of Kansas (KU) US United States (USA) (US) Rutgers Cancer Institute of New Jersey US United States (USA) (US) Oregon Health and Science University (OSHU) US United States (USA) (US) University of Virginia (UVA) US United States (USA) (US) Duke University US United States (USA) (US)

How to cite

APA:

Cuellar-Partida, G., Lu, Y., Dixon, S.C., Fasching, P.A., Hein, A., Burghaus, S.,... Macgregor, S. (2016). Assessing the genetic architecture of epithelial ovarian cancer histological subtypes. Human genetics, 135(7), 741-56. https://dx.doi.org/10.1007/s00439-016-1663-9

MLA:

Cuellar-Partida, Gabriel, et al. "Assessing the genetic architecture of epithelial ovarian cancer histological subtypes." Human genetics 135.7 (2016): 741-56.

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