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

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.