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Ovarian cancer (OC) represents the most dismal gynecological cancer. Pathobiology is poorly understood, mainly due to lack of appropriate study models. Organoids, defined as self-developing three-dimensional in vitro reconstructions of tissues, provide powerful tools to model human diseases. Here, we established organoid cultures from patient-derived OC, in particular from the most prevalent high-grade serous OC (HGSOC). Testing multiple culture medium components identified neuregulin-1 (NRG1) as key factor in maximizing OC organoid development and growth, although overall derivation efficiency remained moderate (36% for HGSOC patients, 44% for all patients together). Established organoid lines showed patient tumor-dependent morphology and disease characteristics, and recapitulated the parent tumor's marker expression and mutational landscape. Moreover, the organoids displayed tumor-specific sensitivity to clinical HGSOC chemotherapeutic drugs. Patient-derived OC organoids provide powerful tools for the study of the cancer's pathobiology (such as importance of the NRG1/ERBB pathway) as well as advanced preclinical tools for (personalized) drug screening and discovery. ; We thank the UZ/KU Leuven Genomics Core for their expert assistance in array CGH analysis, and Thomas Van Brussel (D.L.'s group) for technical help in genome sequencing. We are grateful to Lara Vankelecom (University of Ghent, Faculty of Psychology and Educational Sciences, Department of Data Analysis) for expert help with statistical analyses. The computational resources and services used for genome sequencing and analysis were provided by the Flemish Supercomputer Center (VSC), funded by the Hercules Foundation and the Flemish Government, Department of Economy, Science and Innovation (EWI). We are also grateful to InfraMouse (VIB-KU Leuven, Hercules type 3 project ZW09-03) for use of histological instruments and microscopes. This work was supported by grants from the KU Leuven Research Fund and from the Fund for Scientific Research (FWO) - Flanders (Belgium). N.M. is, and B.C. was, a PhD Fellow of the FWO. D.T. is a Senior Clinical Investigator of the FWO.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Download ; Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer. Keywords: GWAS; TWAS; breast cancer subtype; causal gene. ; Cancer Research UK European Union's Horizon 2020 Research and Innovation Programme European Union (EU) United States Department of Health & Human Services National Institutes of Health (NIH) - USA Cancer UK Genome Canada Canadian Institutes of Health Research (CIHR) Ministere de l'Economie, Science et Innovation du Quebec through Genome Quebec Quebec Breast Cancer Foundation United States Department of Health & Human Services National Institutes of Health (NIH) - USA Post-Cancer GWAS initiative (GAME-ON initiative) Department of Defence Canadian Institutes of Health ...