Tissue-Specific Prevalence and Clonal Architecture of BRCA1/2 LOH-Inducing Chromosomal Aneuploidy

ABSTRACT Germline pathogenic variants in BRCA1 and BRCA2 confer disproportionately elevated cancer risks in breast and ovarian tissues, yet the basis for this tissue specificity remains incompletely understood. Here, we integrate bulk-tumor aneuploidy analysis across 340,824 cancer cases from three independent cohorts (TCGA, ICGC PCAWG, and FoundationCore) with single-cell whole-genome sequencing from two independent studies to investigate whether tissue-specific patterns of chromosomal deletion contribute to this phenomenon. We find that breast and ovarian cancers are consistently enriched for deletions of chromosome arms 17q and 13q—harboring the BRCA1 and BRCA2 genes, respectively—relative to other solid tumor types, and that mutational timing analysis independently places these deletions among the earliest somatic events in these cancers. Phylogenetic reconstruction of single-cell data reveals that in pre-malignant breast tissue from germline BRCA1/2 carriers, chr17q and chr13q deletions appear as localized subclonal events within small clades against a largely diploid background. In established malignancies, these same deletions are found within dominant clonal lineages accompanied by widespread genomic instability—consistent with clonal sweeps originating from early deletion events. These findings suggest that breast and ovarian cellular environments confer a selective advantage for chr17q and chr13q deletions, providing a mechanism that may contribute to the tissue-specific cancer risk observed in gBRCA1/2 carriers. Competing Interest Statement K.H. is a co-founder and board member of a not-for-profit organization, Open Box Science, where he does not receive any compensation. S.D.S. and S.S. are employees at Foundation Medicine, Inc., with an equity interest in Roche. T.J. is an employee of Genentech and a Roche stockholder. All other authors declare no competing interests.