Abstract 5934: Genomic signatures of chromosomal instability from a pan-cancer landscape of haplotype-specific copy-number alterations

Abstract Whole-chromosome and segmental copy-number changes are nearly ubiquitous in human cancers. Here, we present the first pan-cancer landscape of haplotype-specific somatic copy number alterations (SCNAs) in nearly 9,000 cancers across 30 cancer types from The Cancer Genome Atlas (TCGA) whole-genome sequencing (WGS) data. This analysis was primarily carried out with CancerVision, a proprietary bioinformatic workflow for detecting both somatic and germline variants in cancer samples developed by Inocras. The haplotype-specific copy-number analysis provides three pieces of information not available from previous analysis. First, the haplotype-specific SCNAs enables a more accurate assessment of aneuploidy, i.e., the fraction of the cancer genome with copy number alterations. Second, the haplotype resolution directly resolves interactions between germline variant genotypes and SCNAs. Finally, haplotype-specific SCNAs directly inform the instigating mechanisms of chromosomal instability. In this study, we provide examples demonstrating each scenario. Notably, we observed a diverse range of haplotype-specific SCNA patterns, each reflecting a distinct mechanism of chromosomal instability, including arm-level alterations related to WGD, segmental changes indicative of breakage-fusion-bridge (BFB), complex rearrangements displaying signatures of successive BFB cycles and chromothripsis, as well as focal amplifications consistent with extrachromosomal DNA (ecDNA) formation. Our analysis of haplotype-specific SCNAs in TCGA suggests a mechanism-based classification of copy-number patterns linked to chromosomal instability. Extending this framework to treatment-exposed samples could provide new insights into synthetic lethality dependencies, with potential diagnostic and therapeutic implications for cancer precision medicine. Citation Format: Chunyang Bao, Matthew Leventhal, Hansol Park, Gang-Hee Lee, Ryul Kim, Won-Chul Lee, Jonghoon Lee, Yoonsuh Lee, Beomki Lee, David Lehotzky, Ron Solan, Antonia Kowalewski, Xavi Loinaz, Vasuki Narasimha Swamy, David I. Heiman, Samantha Van Seters, Saveliy Belkin, Sam Wiseman, Andrew D. Cherniack, Luis Antonio Corchete Sanchez, Brian P. Danysh, Zachary Everton, Chip Stewart, Haruna Tomono, Gengchao Wang, Esther Rheinbay, Gad Getz, Cheng-Zhong Zhang, Young Seok Ju. Genomic signatures of chromosomal instability from a pan-cancer landscape of haplotype-specific copy-number alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5934.