Abstract 1513: A multi-sample study reveals the evolution and heterogeneity in high-grade serous ovarian cancer

Abstract

Abstract Ovarian cancer is a heterogeneous disease and high-grade serous carcinoma (HGSC) accounts for 70% of them. The pathogenesis of HGSC had remained obscure until the identification of its tubal origin; however, the carcinogenesis process remains largely underexplored. Meanwhile, targeted therapy using poly(ADP-ribose) polymerase (PARP) inhibitors have revolutionized the treatment of HGSCs and emphasizes the importance of patient stratification. Nonetheless, current clinical trials use different assays and a consensus approach for patient stratification is still lacking. In this study, whole genome sequencing technique was used to profile tumor-normal sample pairs, including some related tumors collected from different anatomical sites. This yields a multi-sample cohort comprising 55 pre-treatment samples from 33 HGSC patients and is suitable for addressing questions about molecular stratification and tumor pathogenesis. We first recapitulated two reported HGSC subgroups (H-HRD and H-FBI) in our cohort. Comprehensive analyses were conducted on genomic scars ranging from mutations, indels, structural variants and copy numbers. Our data suggests that the genomic subgroups are characterized by different extent and onset timing of homologous recombination repair defect (HRD) as well as CCNE1 activation. Of note, H-HRD group showed higher levels of copy number-based HRD score, which often serves as a surrogate biomarker for PARP inhibitor treatment response. On the other hand, tumor evolutionary trajectory was reconstructed based on in silico methods capable of inferring relative timing of genetic alterations. This highlights an early bifurcation of carcinogenesis paths in this HGSC dichotomy, despite a common scenario of a very early TP53 mutation, an often early whole genome duplication and a chromosomal instability phenotype seen eventually. Overall, these findings corroborate the concept of tumor-intrinsic genomic phenotypes by providing mechanistic underpinnings from the aspect of tumor evolution. This provides the rationale for studying HGSC disease biology in different contexts and formulating questions about subtype-specific pathogenesis and vulnerabilities. Translationally, it also holds the promise for better identifying the patient subset that might benefit from PARP inhibitor treatment. Citation Format: Siao-Han Wong, Kai Doberstein, Frederik Marmé, Benedikt Brors. A multi-sample study reveals the evolution and heterogeneity in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1513.