KEY POINTS
- Investigators integrated experimental radiosensitivity and transcriptomic datasets with clinical TCGA data to ask whether tumoral loss of the Y chromosome (LOY) could influence radiotherapy response.
- Among 125 male cancer cell lines with curated Y-chromosome status, 47 were LOY-positive. LOY lines had significantly greater survival after 2 Gy, with mean SF2 rank 78.8 versus 53.5 (p<0.001), consistent with a more radioresistant phenotype.
- LOY was subsequently predicted in 392 of 672 DepMap male cell lines (58.3%). Its transcriptional phenotype involved DNA-damage response, senescence, longevity, proliferation and metabolic pathways.
- The clinical analysis included 537 male radiotherapy-treated patients across multiple TCGA tumor types; 102 patients (19.0%) had LOY-positive tumors.
- LOY was associated with worse overall survival in the unadjusted analysis (HR 1.61, 95% CI 1.12–2.31; p=0.01). In the conventional adjusted model the association disappeared (HR 1.38; p=0.23).
- After restriction to a common-support population and propensity overlap weighting, LOY again associated with worse OS (HR 1.74, 95% CI 1.03–2.95; p=0.04). Adding histological grade reduced the cohort to 158 patients and again rendered the association non-significant (HR 1.56; p=0.19).
CLINICAL TAKEAWAY
LOY is an intriguing candidate biomarker of radioresistance, with coherent experimental and biological signals. The clinical evidence is much less secure: survival associations changed depending on the adjustment strategy, and the dataset lacked detailed radiotherapy parameters and systemic-treatment information.
SOURCE
International Journal of Radiation Oncology, Biology, Physics