Tumor Loss of the Y Chromosome Defines a Biological Phenotype Associated with Resistance to Radiotherapy Across Cancer Types.

PURPOSE: Sex-linked determinants of radiotherapy response remain poorly understood. We investigated whether tumor loss of the Y chromosome (LOY) is associated with biological and clinical features of radiotherapy resistance across cancer types. MATERIALS AND METHODS: We integrated publicly available cancer cell-line experimental datasets and clinical data to evaluate the impact of LOY on radiotherapy response. The radiosensitivity of 125 cancer cell lines, stratified by Y chromosome status, was analyzed. Gene expression analyses were performed to identify biological pathways associated with LOY. Clinical associations were examined in 537 male patients treated with radiotherapy across multiple tumor types in The Cancer Genome Atlas. RESULTS: LOY was associated with increased post-radiotherapy survival in cancer cell lines (p < 0.001). Transcriptomic analyses demonstrated LOY-associated alterations in DNA damage response, senescence, longevity, and proliferation pathways. In TCGA tumors, LOY was associated with remodeling of the tumor microenvironment, including altered immune and stromal signatures. Clinically, LOY was associated with inferior survival in common-support overlap-weighted analyses adjusted for age, tumor stage, and TCGA-defined tumor type. CONCLUSION: These findings suggest that tumor LOY is associated with a distinct biological profile characterized by features of radioresistance and adverse clinical outcomes following radiotherapy. Further studies are warranted to determine whether LOY represents a clinically relevant sex-linked determinant of radiotherapy response.