Abstract 3506: High-grade serous ovarian cancer somatic mutational signatures in Black and White individuals
Authors: Lawson-Michod Katherine A. , Nix David , Collin Lindsay , Davidson Natalie , Hippen Ariel , Huff Chad , Atkinson Aaron , Salas Lucas A. , Peres Lauren , Greene Casey , Schildkraut Joellen , Marks Jeffrey , Doherty Jennifer A. 
Published: April 2023

Abstract
Causes of racial disparities in ovarian cancer survival are likely multifactorial, including socio-environmental, structural, and biological factors. Mutational signatures reflect endogenous and exogenous exposures, which may differ by race and ethnicity. This study aims to characterize mutational signatures and their associated etiologies among Black high-grade serous ovarian cancer (HGSC) cases, and to compare the occurrence and distribution of signatures with White TCGA cases. Mutational profiling with whole exome sequencing in matched blood and tumor formalin-fixed paraffin-embedded specimens was performed in 271 HGSC cases identifying as Black or African American and participating in the African American Cancer Epidemiology Study (AACES) or the North Carolina Ovarian Cancer Study (NCOCS). After filtering, we identified 28,601 high-confidence coding mutations in 256 samples that passed quality control assessments. The median number of mutations per sample was 67, similar to that in TCGA at 66. Mutation frequencies of the major genes identified in TCGA were nearly identical in Black AACES/NCOCS cases; mutations in TP53 were present in 96% and 89%, respectively, and mutation frequencies in BRCA1/2, CSMD3, NF1, CDK12, FAT3, GABRA6, and RB1 differed by only 0-2%. We performed mutational signature analysis using SigProfiler and refitting to the Catalogue of Somatic Mutations in Cancer (COSMIC) previously published single base-pair substitution (SBS) signatures reflecting mutational processes resulting from known endogenous and exogenous exposures. SBS signatures are defined by 96 mutation features including the single nucleotide variant class (e.g., C&gt;A, C&gt;G, C&gt;T, T&gt;A, T&gt;C, and T&gt;G) and the identity of the 5’/3’ flanking bases. We observed much higher frequencies of the mismatch repair deficiency, homologous recombination deficiency, ultraviolet light, and treatment exposure signatures in Black AACES/NCOCS cases (26%, 22%, 9%, and 8%, respectively) than in White TCGA cases (3%, 10%, 3%, and 2%, respectively). The frequencies of the remaining signatures with known etiologies (clock-like, reactive oxygen species, base excision repair, mutagen exposure, DNA polymerase epsilon, and tobacco signatures) differed by less than 5% between Black and White cases. Many mismatch repair deficiency signatures identified in Black AACES/NCOCS cases are dominated by C&gt;T or T&gt;C mutations and may represent an artifact from formalin fixation. While we observed that the somatic mutation frequencies in major genes associated with HGSC were similar in Black and White cases, the frequencies of some known mutational signatures were considerably higher in Black HGSC. In particular, despite similar frequencies of BRCA1/2 mutations, the homologous recombination deficiency signature was considerably more common in Black than White HGSC.
Citation Format: Katherine A. Lawson-Michod, David Nix, Lindsay Collin, Natalie Davidson, Ariel Hippen, Chad Huff, Aaron Atkinson, Lucas A. Salas, Lauren Peres, Casey Greene, Joellen Schildkraut, Jeffrey Marks, Jennifer A. Doherty. High-grade serous ovarian cancer somatic mutational signatures in Black and White individuals [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 3506.