Beyond sex determination: the Y chromosome in male cancers

Loss of the Y chromosome (LOY) is the most prevalent somatic genomic alteration in males and can be detected in both blood and other tissues. Age, environmental exposures, mitotic errors and genetic predisposition converge to drive LOY, often via clonal expansion. Emerging evidence has linked LOY to susceptibility, progression and poor outcomes in multiple cancer types. Here we summarize Y-chromosome evolution, structure and gene content, which is essential for male development, transcriptional regulation, chromatin remodelling, and immune and androgen signalling. We highlight the associations of Y-encoded genes with cancer, spanning increased risk in haematological malignancies to context-dependent prognostic impact of LOY in solid tumours. We discuss functional studies, from CRISPR-induced LOY in cell lines and mouse models to bioinformatic analyses of human cohorts, demonstrating the direct effects of LOY on immune surveillance, DNA repair, metabolism and tumour immune microenvironment remodelling. Collectively, these findings indicate that LOY has context-dependent roles in cancer, but whether LOY is a causal, cooperative or passenger event remains unresolved. Advances in bulk and single-cell sequencing, together with LOY scoring algorithms and non-invasive sampling of blood, urine and buccal cells, now enable precise quantification and longitudinal monitoring, offering new opportunities to relate LOY dynamics to disease risk and progression. Finally, we discuss the implications of LOY as a biomarker for cancer risk and precision therapy, including immunotherapy response and treatment stratification.