Abstract 4170: Combination of germline and tumor testing yields a high rate of loss-of-function variants in non-mucinous epithelial ovarian cancer patients
Authors: Fostira Florentia , Kalfakakou Despoina , Papamentzelopoulou Myrto S. , Delimitsou Aggeliki , Apostolou Paraskevi , Vagena Andromachi , Papadimitriou Christos , Aravantinos Gerasimos , Fountzilas Georgios , Yannoukakos Drakoulis , Kostantopoulou Irene 
Published: August 2019

Non-mucinous epithelial ovarian cancer diagnosis is a stand-alone criterion for genetic testing referral, irrespectively of family history or age at diagnosis. Identification of at least BRCA1 & BRCA2 mutations are fundamental for clinical decision making of ovarian cancer (OC) patients. The purpose of our study was to evaluate the prevalence of damaging variants that can lead to defects of DNA repair by homologous recombination (HR) in an unselected cohort of epithelial non-mucinous OC patients. Identification of such variants can indicate ideal candidates for Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor therapies.We therefore comprehensively analyzed genomic DNA from 578 epithelial non-mucinous OC patients for mutations in 94 genes that are involved in DNA repair, implementing a commercially available gene-panel. Additionally, 121 tumors were collected from OC patients that had negative germline testing and were assessed for somatic BRCA1 & BRCA2 mutations. Tumor cell content and necrosis were evaluated prior to tumor DNA extraction and were above 50% and below 20%, respectively.Overall, 25.4% (147/578) of the patients carried germline loss-of-function (LoF) variants, distributed in 18 genes namely, BRCA1, BRCA2, RAD51C, ATM, FANCL, CHEK2, FANCM, BRIP1, TP53, NBN, FANCA, RECQL4, MLH1, MSH2, MSH6, PMS2, ERCC2 and SLX4. After BRCA1 & BRCA2, which accounted for 72.1% of the total LoF variants, RAD51C LoF variants were the most frequent, accounting for 4.8% of the total LoF variants. Interestingly, the vast majority of LoF variants (136/147; 92.5%) involved homologous recombination/Fanconi anemia genes, detected in 23.5% of the total OC patients tested. Notably, 4.5% of the pathogenic variants were detected in genes involved in Mismatch Repair (MMR) pathway. Subsequently, tumor analysis resulted in the identification of damaging BRCA1 & BRCA2 variants in 11.5% of the ovarian tumors tested. Variant allele frequencies varied from 9%-47%. Altogether, approximately one in three of OC patients in our cohort could be good candidates for therapies targeting defective mechanisms of DNA repair, including HR and MMR.Our study highlights the high prevalence of LoF variants in HR genes, when combining germline and tumor testing in unselected, non-mucinous epithelial OC patients. These genetic defects can predominantly lead to HR deficiency, the ultimate biomarker for therapeutic intervention by PARP inhibition leading to tumor-cell death.

Citation Format: Florentia Fostira, Despoina Kalfakakou, Myrto S. Papamentzelopoulou, Aggeliki Delimitsou, Paraskevi Apostolou, Andromachi Vagena, Christos Papadimitriou, Gerasimos Aravantinos, Georgios Fountzilas, Drakoulis Yannoukakos, Irene Kostantopoulou. Combination of germline and tumor testing yields a high rate of loss-of-function variants in non-mucinous epithelial ovarian cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4170.