Loss of the Y chromosome is transcriptionally silent in clear cell renal cell carcinoma and across cancer entities

Tumors in men often lose the Y chromosome. In some tumor types, this is predictive of poor outcome. Given the male predominance and high LOY frequency in clear cell renal cell carcinoma (ccRCC), we asked whether LOY might impact the transcriptome of ccRCC. We determined somatic Y chromosome status and performed differential expression analysis on tumor RNA-sequencing samples of two human ccRCC cohorts (TCGA-KIRC, CPTAC-ccRCC) and in an autochthonous murine ccRCC model with renal epithelium-specific deletion of Vhl, Trp53 and Rb1. We additionally derived five isogenic Y-deficient and five Y chromosome-retaining clones of the human ccRCC cell line 786-O. Across all three settings, transcriptional changes were largely restricted to the expected gene dosage effects of male-specific Y (MSY) and pseudoautosomal region (PAR) genes, without large effects on autosomal genes. At the pathway level, we identified a modest but reproducible response in the human cohorts, converging on cell cycle, ribosomal biogenesis and DNA repair genes. A pan-cancer meta-analysis across TCGA entities recovered the same pattern, with no autosomal gene showing a large consistent effect. In some entities, but not in ccRCC, cancer/testis antigen expression was higher in LOY tumors. We conclude that, apart from direct gene dosage, modest pathway-level shifts and altered silencing of cancer/testis antigens, LOY is transcriptionally silent in adult humans and mice. Y-chromosomal genes are therefore unlikely to act as transcriptional drivers of ccRCC and other cancer entities.