<p>Mosaic loss of Y chromosome is a common genetic phenomenon in elderly men. It predisposes affected individuals to cancers, suggesting that genes on this male-specific chromosome contribute to the well-being of men. Currently, the putative gene(s) responsible for such cancer predisposition when lost is/are currently unknown. A recent study identified the testis-specific protein Y-encoded (TSPY) gene possesses significant immunogenicity, capable of eliciting significant immune responses against and eliminating positive tumor cells in a mouse model of liver cancer. TSPY is a male-specific cancer-testis antigen expressed in a wide variety of cancers but not normal somatic cells. It is an ampliconic gene constituting a majority (~ 42%) of all protein-coding genes on the human Y chromosome. TSPY is hypothesized to be a guardian gene for man, protecting man from cancer development. Its high copy-number of conserved functional units ensures that it is intrinsically activated in early/progenitor cancer cells, thereby eliciting robust immune responses, eliminating early tumor progenitor cells and preempting oncogenic progression and tumor development. Loss of TSPY gene cluster together with the loss of the entire Y chromosome in oncogenic progenitor/early tumor cells provide a favorable environment fostering oncogenic development, thereby predisposing elderly men to cancers.</p>