Abstract 4336: Homologous recombination repair deficiency, and not recurrence, determines mutational burden and clonal dynamics in high grade serous ovarian cancer
Authors: Diaz Michael A. , Gull Nicole , Peng Pei-Chen , Lawrenson Kate , Rimel Bobbie J. , Lester Jenny , Karlan Beth , Gayther Simon A. , Jones Michelle R. 
Published: March 2024

Abstract
High grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy, killing more than 9,000 women each year in the United States. Nearly 80% of patients with HGSOC will experience recurrence within 5 years, but little is known about the mechanisms that drive this process. Up to 60% of the genome in an HGSOC tumor is impacted by structural variant mutations and pronounced intratumoral heterogeneity. Intratumor heterogeneity is believed to be a key feature of recurrence and therapy resistance with some evidence indicating diverse and complex mechanisms of the seeding of metastatic sites and recurrent tumors. We included 35 HGSOC patients for whom paired chemo-naive and chemoresistant tumors as well as germline DNA was available. Whole genome sequencing was used to identify somatic single nucleotide variants (SNV) insertion/deletion variants (indels), and structural variants (SVs) in each tumor. The number of somatic SVs and indels was higher in tumors with homologous recombination repair deficiency (HRD; P=0.000252 SVs, P=0.00385 Indel) but was not affected by recurrent status (P=0.826 SV, P=0.145 SNV/indel). Clonal composition and dynamics were measured using SNVs/indels as tumors progressed from chemo-naïve primary samples to recurrent chemo-resistant tumors. Surprisingly, few changes were observed in clonal abundance and complexity through progression. When this analysis was repeated with SVs homologous recombination repair proficient tumors tend to be polyclonal while HRD tumors tend to be monoclonal. Five denovo structural variant signatures were identified in our cohort and led to three distinct structural variant classes tumors defined by deletion, tumors defined by duplication, and tumors defined by copy number neutral changes (inversions, translocations and balanced complex events). Patients with tumors defined by deletions and copy number neutral changes carry pathogenic SVs correlating with reduced survival (P=0.00023), while DNA gains are less subject to pathogenic alterations. Each class displayed distinct regions of the chromosome that was frequently affected by large scale SV events (&gt;5Mb), which was also observed in the HRP/HRD status. Although no regions were notably altered across recurrence, GO analysis revealed that recurrent tumors have a significantly reduced immune response, which was not seen in the primary tumors. Within a subset of tumors, we are plan to utilize Oxford Nanopore Technologies ultra long read sequencing which will allow for confirmation of SVs observed in the WGS as well as identification of more complex events that cannot be deciphered using WGS techniques.
Citation Format: Michael A. Diaz, Nicole Gull, Pei-Chen Peng, Kate Lawrenson, Bobbie J. Rimel, Jenny Lester, Beth Karlan, Simon A. Gayther, Michelle R. Jones. Homologous recombination repair deficiency, and not recurrence, determines mutational burden and clonal dynamics in high grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4336.