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

Abstract

Background Loss of the Y chromosome (LOY) is the most frequent somatic alteration in male cancers and has recently been linked to immune evasion, metabolic reprogramming and prognosis. Because the Y chromosome encodes transcriptional and epigenetic regulators, such as UTY and KDM5D, LOY is assumed to act through dysregulation of autosomal gene expression. We asked whether LOY produces a transcriptional signature in clear cell renal cell carcinoma (ccRCC), where about 40% of male tumors lose the Y chromosome. Methods Here, we inferred Y chromosome status from RNA-sequencing of male ccRCC in TCGA-KIRC (n = 289) and CPTAC-ccRCC (n = 114), in 32 tumors from an autochthonous Vhl/Trp53/Rb1-deficient mouse model, and in five isogenic Y-deficient and five Y-retaining clones of the 786-O cell line. Differential expression was tested with Wilcoxon rank-sum tests on age- and purity-adjusted residuals combined by Stouffer meta-analysis (human cohorts) or with DESeq2 (mouse, cell clones), followed by gene set enrichment analysis. Pseudoautosomal genes, present on both sex chromosomes, served as internal controls for a halving of gene dosage. Results In all three settings, transcriptional changes were confined to the expected dosage effects of male-specific Y and pseudoautosomal genes. No autosomal gene reached the significance level of the non-compensated pseudoautosomal genes in human ccRCC, 14 autosomal genes were altered in the mouse model and 40 in the isogenic 786-O clones, none shared across settings. Gene set enrichment analysis revealed a modest, reproducible upregulation of cell division, ribosome biogenesis and DNA repair pathways shared between human and murine ccRCC. A meta-analysis across 27 male TCGA cancer entities (1,710 LOY, 2,988 Y-retaining tumors) recovered the same pattern with no autosomal gene showing a consistent large effect, and the same cell division, ribosome biogenesis and DNA repair pathways were modestly upregulated. Cancer/testis antigen expression was elevated in LOY tumors of several entities, most notably stomach adenocarcinoma, but not ccRCC. Conclusions Beyond direct gene dosage, LOY leaves the transcriptome of ccRCC, and of most other cancer entities, essentially unchanged. Y-encoded genes are therefore unlikely to drive cancer through direct transcriptional regulation of autosomal genes, directing attention to non-transcriptional effects of LOY.