Y-chromosome alteration and its impact on cancer progression and metastasis

The human Y chromosome (ChrY), which confers male sex determination, contains a relatively small number of protein-coding genes compared to other chromosomes; consequently, its functional impact on adult physiology was once severely unappreciated. While the repetitive structure of the ChrY once impeded sequencing, technological advances have now made it possible to identify its contents. Despite the historical view of ChrY as a virtual wasteland, we now know that it encodes a variety of genes which are hugely consequential to both human health and disease. The extreme downregulation of ChrY gene expression, resulting from partial or total loss of ChrY (LOY), is a common characteristic observed in various disease states in men, including cardiovascular, neurodegenerative, immunological health issues, and ,most notably, cancer. Additionally, mosaic LOY (mLOY) is sometimes found in primary cancerous tissues and is associated with poorer clinical outcome. Although, the reasons for these associations were once elusive, they are now understood to be linked to the activity of several ChrY genes, as well as the pleiotropic effects of their loss. In this review, we critically analyze contemporary and historic scientific literature which evaluate the clinical LOY trends seen in male exclusive/predominant cancers as well as explore the now identified mechanisms of ChrY alteration in cancer initiation, progression, and metastasis. Moreover, we discuss recent research studies which have uncovered novel mechanisms through which LOY may induce the physiological and molecular changes in the tumor microenvironment (TME) associated with malignant transformation and the evasion of innate immunity. Interestingly, the TME formed by malignant cells with LOY appears to contribute to early T cell exhaustion in infiltrating immune cells and consequent compromised tumor clearance; a phenomenon which has been profusely observed in patient samples. Furthermore, we describe the tumor-suppressive activities of the ChrY demonstrated in previous studies, as well as its newly identified roles in cancer immunology.