The pan-cancer landscape of chromosome Y alterations

Background : Despite the well-documented male bias in the incidence and mortality of most non-sex-specific cancers, the Y chromosome (chrY) remains as a genomic blind spot. Major pan-cancer genomic consortia, including The Cancer Genome Atlas (TCGA) and PCAWG, have historically excluded the chrY from somatic analyses due to computational challenges related to its haploid state, repetitive structure, and homology with the X chromosome. Consequently, the somatic landscape of chrY alterations, including complete loss of Y (LOY), structural variants (SVs), single-nucleotide variants (SNVs), and INDELs, remains largely uncharacterized. Methods : We implemented a pan-cancer computational framework utilizing deep whole-genome sequencing (WGS) data from a comprehensive re-analysis of 26 cancer types from the TCGA cohort. We developed and applied a novel bioinformatic pipeline to accurately call somatic LOY, complex SVs, SNVs, and INDELs. The pipeline was specifically designed to overcome analytical challenges of the chrY, including its repetitive structure and the correct handling of pseudoautosomal regions (PARs). Potential artifacts were flagged using variant-support metrics and by identifying breakpoints in problematic regions. Results : The analysis revealed a highly heterogeneous landscape of chrY alterations across tumor types. We found a high prevalence of somatic SVs in some tumor types, such as bladder (BLCA), head and neck (HSNC), stomach (STAD), and prostate (PRAD) cancers, while others, like thyroid (THCA) and renal clear cell carcinoma (KIRC), were rarely affected. In affected tumors, the SV landscape included numerous inter-chromosomal translocations, which often showed low variant allele frequency (VAF), suggesting a subclonal origin. In contrast, the clonality of chrY deletions varied across cancer types. The SNV/INDEL burden was substantial in certain cancers, for example, in glioblastoma (GBM) and PRAD, but was concentrated in non-coding regions, with protein-coding mutations being infrequent. Interestingly, we observed a chrY SNV spectrum enriched in C>T and T>C substitutions across several tumor types. Conclusion : We developed a computational framework to systematically analyze the Y chromosome across multiple cancer types, overcoming historical analytical challenges. Our results reveal a diverse spectrum of somatic alterations, including structural variants and point mutations. These findings provide the first comprehensive, pan-cancer map of the somatic chrY landscape.