Abstract 2510: High-depth whole genome sequencing of clinically-annotated high-grade serous ovarian cancers
Authors: Sanghoon Lee, Li Zhao, Shannon N. Westin, Nicholas W. Bateman, Amir A. Jazaeri, Nicole D. Fleming, Karen H. Lu, Robert L. Coleman, Gordon B. Mills, Jianhua Zhang, Thomas P. Conrads, George L. Maxwell, P. Andrew Futreal, Anil K. Sood
Journal: Cancer Research (2020)

Abstract Background: Prior molecular characterization efforts for high-grade serous ovarian cancer (HGSOC) were restricted to those who had upfront surgical debulking with variable treatment paradigms. Thus, we sought to examine molecular and cellular differences between clinically defined groups (tumor tissues from patients who had complete gross resection (CGR) versus those who were triaged to neoadjuvant chemotherapy (NACT) and experienced either excellent or poor response. Methods: Tumor biopsies were collected from three patient groups managed under a systematic surgical algorithm: CGR after primary surgery (R0, n=10); poor tumor response to NACT (NACT-PR, n=10); excellent tumor response to NACT (NACT-ER, n=10). Primary and multiple metastatic tumor sites per each patient were obtained pre-treatment and subjected to comprehensive omics analyses including high-pass whole-genome (WGS) and targeted deep DNA sequencing. Results: An average of 71 nonsynonymous somatic mutations from each sample for 75 samples with high-purity tumors (≥75%) by WGS were identified from each sample for the entire cohort. Fourteen ovarian-cancer-associated genes were found mutated in our patient cohort and, as expected, the most frequently mutated gene was TP53 in both primary and metastatic sites in all three groups. TP53 nonsense mutations were exclusively identified in the NACT-ER (36.0%) and NACT-PR groups (15.4%), while in the R0 group most TP53 mutations were missense mutations (62.5%). Nonsense mutations in CSMD3 and PIK3CA were exclusively identified in both primary and metastatic sites in the NACT-PR group. The most frequent copy number variations (CNVs) in the R0 were copy number gain/loss of CSMD3 (67%) and copy number loss of NF1 (54%) and CDK12 (50%) in both primary and metastatic sites. Interestingly, copy number losses of NF1 were significantly lower in the NACT groups (18%, p=0.002), especially in the NACT-PR (8%, p=0.0004), when compared to the R0 group (54%). We also identified significant less observation of chromothripsis-like patterns, and a significantly higher level of strong-binding neoantigens in the R0 than in the NACT groups. Conclusions: Our findings using HGSOC samples obtained from patients treated on a prospective algorithm identified distinct molecular abnormalities, and could have prognostic and therapeutic implications for patients with HGSOC. Citation Format: Sanghoon Lee, Li Zhao, Shannon N. Westin, Nicholas W. Bateman, Amir A. Jazaeri, Nicole D. Fleming, Karen H. Lu, Robert L. Coleman, Gordon B. Mills, Jianhua Zhang, Thomas P. Conrads, George L. Maxwell, P. Andrew Futreal, Anil K. Sood. High-depth whole genome sequencing of clinically-annotated high-grade serous ovarian cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2510.