Abstract IA009: Scars of faulty DNA repair in cancer whole genomes

Abstract

Abstract Cancer genomes provide a record of the genetic alterations acquired from DNA damage and DNA repair defects during normal cell development and carcinogenesis. Genome-wide somatic alteration patterns in BRCA1-deficient (BRCA1d) and BRCA2-deficient (BRCA2d) cancers are attributed to a deficiency in homologous recombination (HR), a major pathway for the repair of double-strand breaks (DSBs) in human cells. Some of these mutational patterns may reflect specific error-prone repair mechanisms of DSB repair that cells use in the absence of HR. Such mutational patterns can provide biomarkers of HR-deficiency and help identify clinically relevant therapeutic vulnerabilities. HRD is has been associated with specific DNA rearrangements and cytogenetic aberrations. Paradoxically, the types of DNA rearrangements specifically associated with HR-deficient (HRD) cancers only minimally impact chromosomal structure. Addressing this, we combined a genome graph analysis of short-read whole genome sequencing (WGS) profiles across thousands of tumors with deep linked-read (LR) WGS of 46 BRCA1- or BRCA2-mutant breast cancers to discover a distinct class of HR deficiency-enriched rearrangements called reciprocal pairs. LR WGS showed that reciprocal pairs with identical rearrangement orientations gave rise to one of two distinct chromosomal outcomes, distinguishable only with long molecule data. While one (cis) outcome corresponded to the copy and pasting of a small segment to a distant site, a second (trans) outcome was a quasi-balanced translocation or multi-megabase inversion with substantial (10kb) duplications at each junction. We propose an HR-independent replication restart repair mechanism to explain the full spectrum of reciprocal pair outcomes. LR WGS additionally identified single-strand annealing (SSA) as a BRCA2-deficiency specific repair pathway in human cancers. Integrating these features in a classifier improved discrimination between BRCA1- vs. BRCA2-deficient genomes. In conclusion, our data reveal classes of BRCA1- and BRCA2-deficiency specific rearrangements as a source of cytogenetic aberrations in HRD cells. Citation Format: Jeremy Setton, Simon Powell, Marcin Imielinski. Scars of faulty DNA repair in cancer whole genomes [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr IA009.