がん：がんの転帰に性差が生じる機構を解明する

Insights into the role of the Y chromosome on sex differences in cancer outcomes, in which males are often more adversely affected than females, are uncovered in two studies involving animal models and some human data that are published in Nature this week. One paper identifies an upregulated gene on the Y chromosome that contributes to sex differences in colorectal cancer in mice by driving tumour invasion and aiding immune escape in males. The other paper demonstrates that loss of the Y chromosome in bladder cancer generates a more immunosuppressive tumour microenvironment and contributes to worse outcomes. The findings may guide efforts to develop treatments to reduce sex-associated cancer risks.

Sex is known to affect cancer incidence, clinical outcomes and tumour biology, with most cancers causing worse outcomes in males than in females. The sex-specific mechanisms that underlie these disparities are not well understood, but some research has suggested that the function of the Y chromosome may have a role.

Ronald DePinho and colleagues assess sex differences in colorectal cancer — the second most common cause of cancer-related deaths, which is more frequent, aggressive and metastatic in males — in a mouse model of the disease. The model is a specific form of the disease, driven by a known oncogene called KRAS. The researchers observe a higher frequency of metastasis and worse survival in male mice, mirroring the outcomes seen in humans. Analyses reveal upregulation of a gene for an enzyme from the histone demethylase family, which drives tumour invasion and immune escape. This gene is expressed on the Y chromosome, thereby providing a potential basis for sex-specific differences in the progression of KRAS-driven colorectal cancer.

In an independent study, Dan Theodorescu and colleagues investigate how the loss of the Y chromosome might affect cancer outcomes. Loss of the Y chromosome is a feature observed in multiple cancer types, although its clinical and biological significance has been unclear. They first look at clinical data from 300 male patients with bladder cancer to identify an association between Y chromosome loss and poor prognosis. They go on to study bladder cancer cell lines and find that, compared with tumours with Y chromosomes, tumours lacking the Y chromosome were more aggressive and had a dampened T cell-mediated immune response. They note that loss of the Y chromosome is associated with an increased response to a specific type of immunotherapy called anti-PD1 checkpoint blockade therapy in both mice and humans, suggesting a potential line of treatment for this subset of bladder cancers.