Assessing the genetic architecture of epithelial ovarian cancer histological subtypes

Gabriel Cuellar-Partida, QIMR Berghofer Medical Research Institute
Yi Lu, QIMR Berghofer Medical Research Institute
Suzanne C. Dixon, QIMR Berghofer Medical Research Institute
Australian Ovarian Cancer Study, QIMR Berghofer Medical Research Institute
Peter A. Fasching, David Geffen School of Medicine at UCLA
Alexander Hein, Universitätsklinikum Erlangen
Stefanie Burghaus, Universitätsklinikum Erlangen
Matthias W. Beckmann, Universitätsklinikum Erlangen
Diether Lambrechts, Departement Menselijke Erfelijkheid
Els Van Nieuwenhuysen, KU Leuven– University Hospital Leuven
Ignace Vergote, KU Leuven– University Hospital Leuven
Adriaan Vanderstichele, KU Leuven– University Hospital Leuven
Jennifer Anne Doherty, Geisel School of Medicine at Dartmouth
Mary Anne Rossing, University of Washington
Jenny Chang-Claude, German Cancer Research Center
Anja Rudolph, German Cancer Research Center
Shan Wang-Gohrke, Universität Ulm
Marc T. Goodman, Cedars-Sinai Medical Center
Natalia Bogdanova, Medizinische Hochschule Hannover (MHH)
Thilo Dörk, Medizinische Hochschule Hannover (MHH)
Matthias Dürst, Friedrich-Schiller-Universität Jena


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 (hg2 = 8.8 ± 1.1 %), endometrioid (hg2 = 3.2 ± 1.6 %), clear cell (hg2 = 6.7 ± 3.3 %) and all EOC (hg2 = 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.