Cancer more deadly when tumours lack Y chromosomes — and the loss could be contagious

Amazing stuff! Cancer is history (soon)!

Notice that the research article itself is open access, but the two Nature news articles about this research paper have no public access. Weird!

"The cancer cells of some men feature a striking mutation: their Y chromosome is missing altogether. Now, tantalizing research suggests that this mutation can spread ‘contagiously’ from tumour cells to immune cells, which lose their cancer-fighting prowess after their Y chromosome disappears. ..."

From the abstract:

"Loss of the Y chromosome (LOY) in peripheral blood mononuclear cells (PBMCs) is the most common somatic alteration in men and is associated with higher mortality from epithelial cancers.

In tumours, epithelial LOY is also associated with poor survival. This raises several fundamental questions, such as why LOY in PBMCs drives cancer mortality and whether there is a relationship between LOY in PBMCs, PBMC-derived immune cells and cancer cells (and, if so, what its consequences are).

We sought to answer these questions through a comprehensive pan-cancer analysis of bulk and single-cell RNA sequencing data from 29 human tumour types, along with autochthonous and syngeneic mouse models.

In human and mouse tumours, malignant epithelial cells had the highest LOY prevalence, yet LOY was also present in tumour stromal and immune cells, with LOY in malignant epithelial cells predicting LOY in benign cells. LOY also correlated between paired tumour and PBMC samples from patients. Among benign cells, LOY induced the strongest shift in CD4+ and CD8+ T cells, with both showing transcriptomic signatures of immunosuppression. Furthermore, the magnitude of LOY in epithelial cells, CD4+ T cells and CD8+ T cells independently predicts survival, with tumours exhibiting concurrent epithelial and T cell LOY having the worst outcomes. Here we establish a model that links LOY in immune cells to LOY in malignant cells, which may explain in part why LOY in PBMCs is associated with increased cancer mortality."

Cancer more deadly when tumours lack Y chromosomes — and the loss could be contagious (no public access) "Losing the Y chromosome seems to make cancer cells more aggressive in men and the phenomenon might even spread between cells." (very limited public access)

Y-chromosome loss in cancer and immune cells might worsen treatment outcomes (no public access) "Prognosis is poor for tumours with Y-chromosome loss. Examining the interplay between cancer and immune cells sheds light on potential mechanisms."

Concurrent loss of the Y chromosome in cancer and T cells impacts outcome (open access)

Fig. 2: LOY in malignant epithelial cells promotes anaerobic metabolic reprogramming and reduces immunogenicity.