Abstract 733: Characterizing the genetic profile of endometrioid ovarian carcinoma using exome sequencing

Abstract

Abstract Objective: Endometrioid ovarian carcinoma is poorly understood at the genomic level. Prior sequencing investigations have been limited to small gene panels. In order to characterize the etiology of this disease and identify potential therapeutic targets, we sought to build an unbiased genetic profile of coding gene alterations in endometriod ovarian tumors. Methods: We sequenced the exomes of primary endometrioid ovarian tumors obtained from our institutional gynecologic oncology tissue bank from 1996 - 2011. We analyzed somatic point mutations, copy number alterations, structural variations and mutational signatures and integrated these data to determine genetic drivers. Demographic and clinical data were collected by retrospective chart review. Results: Seventeen primary endometrioid ovarian tumors were sequenced. Median age at surgical resection was 51 years (range 33-77 years). The majority of patients presented with early stage disease (71%), many had a history of endometriosis (47%) and 19% had a synchronous primary uterine carcinoma. Microsatellite instability (MSI) was present in 18% (3/17) tumors. All three of these tumors with MSI exhibited a high tumor mutational burden with an average of 174 mutations per megabase of DNA, and two of them had confirmed loss or inactivation of mismatch repair proteins. Approximately half of all cases (47%) had inactivation or truncating mutations in PTEN. 59% of cases (10/17) had alterations in WNT pathway genes, including 6/17 (35%) with missense mutations in the regulatory domain of beta catenin (CTNNB1). 2/17 (12%) had TP53 mutations. We identified one case with a mutation in the exonuclease domain of POLE (P286R), which also exhibited a characteristic POLE-mutant mutation signature. Conclusion: Using whole exome sequencing, we identified that endometrioid ovarian carcinomas are commonly hypermutated and often harbor microsatellite instability. These findings highlight the importance of genetic sequencing to determine which patients may benefit from targeted immunotherapies. Citation Format: William E. Pierson, Pamela Peters, David A. Quigley, Lee-may Chen, Jocelyn S. Chapman. Characterizing the genetic profile of endometrioid ovarian carcinoma using exome sequencing [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 733.