Unveiling the role of SRY in male-biased cancers: Insights into the molecular basis of sex disparities in high-grade glioma and melanoma

Sex disparities have been observed in many tumor types affecting non-reproductive organs. Typically, the incidence and mortality rates of such cancers are higher in men. Although differences in lifestyle and environmental exposures are known contributors, knowledge of the molecular mechanisms driving sexual dimorphism in tumor development and therapy response remains limited. To address this question, we comprehensively studied the sex-determining region Y (SRY) gene, a male-specific gene that is critical in development. First, we screened 2,448 samples from 11 cancer types to identify those with a higher incidence in men and increased expression of SRY. In cases of high-grade glioma and melanoma, men with tumors exhibiting high SRY expression had a worse prognosis. Our results suggest that SRY target genes show altered expression when SRY is overexpressed. These gene sets are linked to cell growth, epithelial-mesenchymal transition, inflammation, and repression of tumor suppressor pathways. In summary, we present the first comprehensive investigation of SRY expression and its association with clinical outcomes in men with high-grade glioma and melanoma. Our results shed light on the molecular basis for sex disparities and lay the foundation for investigation of various target genes and novel cancer treatments in men with high-grade glioma and melanoma.