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Cancer genetics

Explaining the male bias in cancers

Nature Reviews Genetics volume 24, page 661 (2023)Cite this article

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Sex-specific differences in disease prognosis have been observed for many cancer types, including colorectal cancer (CRC) and bladder cancer, with men typically having higher metastasis rates and worse treatment responses than women. Although differences in lifestyle and hormones have been put forward as explanations for the sex bias of these cancers, the role of genetic factors is poorly understood. Now, two independent studies published in Nature suggest that the Y chromosome could explain why certain cancers are particularly aggressive in men.

The authors next explored the mechanisms by which KDM5D promotes metastasis. Profiling of chromatin marks by chromatin immunoprecipitation plus high-throughput sequencing (ChIP–seq) and analysis of gene expression by RNA sequencing revealed that genes involved in the maintenance of tight junctions — cell adhesion complexes that are lost during metastasis formation — were downregulated in metastatic iKAP tumours compared with primary tumours, as were genes that encode components of the major histocompatibility complex (MHC) class I. Further functional experiments showed that genetic deletion of Kdm5d increased the integrity of tight junctions and enhanced cancer cell killing by CD8+ T cells. Overall, these findings show that upregulation of the Y chromosome gene Kdm5d promotes the disruption of cancer cell adhesion and tumour immunity, contributing to male-specific cancer progression.

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References

Original article

  • Li, J. et al. Histone demethylase KDM5D upregulation drives sex differences in colon cancer. Nature 619, 632–639 (2023)

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  • Abdel-Hafiz, H. A. et al. Y chromosome loss in cancer drives growth by evasion of adaptive immunity. Nature 619, 624–631 (2023)

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  1. Nature Reviews Genetics http://www.nature.com/nrg/

    Michael Attwaters

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  1. Michael Attwaters
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Correspondence to Michael Attwaters.

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Attwaters, M. Explaining the male bias in cancers. Nat Rev Genet 24, 661 (2023). https://doi.org/10.1038/s41576-023-00650-5

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  • DOI: https://doi.org/10.1038/s41576-023-00650-5

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