Recurrent deletions and regulatory disruption of the Y chromosome in cancer.

Abstract

Somatic loss of the Y chromosome (LOY) is the most frequent acquired genomic alteration in aging males and occurs across multiple cancer types. While common, its functional role in tumorigenesis is only beginning to emerge. Most studies treat LOY as a binary event, ignoring partial deletions that may selectively remove gene-rich euchromatic regions. To address this, we used high-coverage whole-genome sequencing, large-scale transcriptomics, and eQTL to map male cancer cell lines, eliminating confounding non-malignant cells. We reveal a region-specific LOY landscape with recurrent euchromatic deletions affecting protein-coding genes and non-coding elements. Losses were quantified using a new Y EroSion (YES) Score, which is associated with transcriptional differences and clinical outcome patterns suggestive of functional relevance. Retained Y-linked loci remain transcriptionally active, enriched for proliferation, immune signaling, and stress adaptation functions. These findings position LOY as a structured genomic event with regulatory and clinical implications, motivating validation in primary tumor cohorts.