Concurrent loss of the Y chromosome in cancer and T cells impacts outcome [snRNA-seq]

Loss of the Y chromosome (LOY) in peripheral blood mononuclear cells (PBMCs) is the most common somatic alteration in normal men and is associated with greater mortality from epithelial cancers. In tumors, epithelial cell LOY is also associated with worse survival. This raises the fundamental question of whether a relationship between LOY in PBMCs, PBMC-derived immune cells, and cancer cells exists, and if so, what the consequences are. We addressed this through a comprehensive pan-cancer analysis of bulk and single-cell RNA sequencing data from 29 distinct human tumor types, and from autochthonous and syngeneic murine models of cancer. In both human and murine tumors, malignant epithelial cells had the highest LOY prevalence, which was associated with significant phenotypic changes. Remarkably, LOY was also found in stromal and immune cells of the tumor microenvironment (TME) of both species, with the presence of LOY in malignant epithelial cells predicting LOY in benign cells. In addition, LOY was correlated between paired tumor and PBMC samples from patients. Among benign cells, LOY drove the strongest phenotypic shift in CD4+ T and CD8+ T cells, with both showing signs of immunosuppression. The magnitudes of LOY in epithelial cells, CD4+ T cells, and CD8+ T cells were independent predictors of overall survival, with tumors exhibiting concurrent epithelial and T cell LOY having the worst outcomes. These findings provide a novel model linking LOY in immune and malignant epithelial cells and explain in part why LOY in PBMCs and tumors are both associated with greater cancer mortality. Overall design: Mouse single-nuclei RNA sequencing for hepatocellular carcinoma (HCC) studies was conducted using MUP-uPA+ mice. The mice were fed a Western Diet (Teklad, TD.88137) for 8 months, starting at 8 weeks of age. HCC development was assessed at 10 months of age.