Ovarian cancer (OC) is the deadliest gynecologic malignancy with a substantial proportion of hereditary cases and a frequent association with breast cancer (BC). Genetic testing facilitates treatment and preventive strategies reducing OC mortality in mutation carriers. However, the prevalence of germline mutations varies among populations and many rarely mutated OC predisposition genes remain to be identified. We aimed to analyze 219 genes in 1333 Czech OC patients and 2278 population-matched controls using next-generation sequencing. We revealed germline mutations in 18 OC/BC predisposition genes in 32.0% of patients and in 2.5% of controls. Mutations in BRCA1/BRCA2, RAD51C/RAD51D, BARD1, and mismatch repair genes conferred high OC risk (OR > 5). Mutations in BRIP1 and NBN were associated with moderate risk (both OR = 3.5). BRCA1/2 mutations dominated in almost all clinicopathological subgroups including sporadic borderline tumors of ovary (BTO). Analysis of remaining 201 genes revealed somatic mosaics in PPM1D and germline mutations in SHPRH and NAT1 associating with a high/moderate OC risk significantly; however, further studies are warranted to delineate their contribution to OC development in other populations. Our findings demonstrate the high proportion of patients with hereditary OC in Slavic population justifying genetic testing in all patients with OC, including BTO.

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute 656 53 Brno Czech Republic

Department of Gynecology and Obstetrics Hospital Na Bulovce and 1st Faculty of Medicine Charles University 180 81 Prague Czech Republic

Department of Medical Genetics AGEL Laboratories AGEL Research and Training Institute 741 01 Novy Jicin Czech Republic

Department of Medical Genetics Centre for Medical Genetics and Reproductive Medicine Gennet 170 00 Prague Czech Republic

Department of Medical Genetics GHC Genetics 110 00 Prague Czech Republic

Department of Medical Genetics Pronatal 147 00 Prague Czech Republic

Department of Medical Genetics University Hospital Olomouc Faculty of Medicine and Dentistry Palacky University Olomouc 779 00 Olomouc Czech Republic

Department of Oncology 1st Faculty of Medicine Charles University and General University Hospital Prague 128 08 Prague Czech Republic

Institute of Biochemistry and Experimental Oncology 1st Faculty of Medicine Charles University 128 53 Prague Czech Republic

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University and General University Hospital Prague 128 00 Prague Czech Republic

Laboratory of Cancer Cell Biology Institute of Molecular Genetics of the Czech Academy of Sciences 142 20 Prague Czech Republic

Research Unit for Rare Diseases Department of Pediatrics and Adolescent Medicine 1st Faculty of Medicine Charles University and General University Hospital Prague 12808 Prague Czech Republic

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