Two studies indicate that the Y chromosome influences in the differences between sexes with respect to cancer.
Beyond the possible impact of lifestyle differences between men and women, there is a genetic reason why most cancers have a more adverse effect on men than on women. Two recent studies published in the journal Nature, They suggest that the function of the Y chromosome, essential for the determination of male sex, influences men's greater vulnerability to cancer.
The first study links the loss of the Y chromosome observed in some bladder tumors to tumor aggressiveness. The second suggests that the expression of a gene located on the Y chromosome may promote metastasis in colorectal cancer. Furthermore, in both cases, alterations in the immune system are central to the involvement of the Y chromosome.
The results provide new insights into the role of the Y chromosome in tumor progression, as well as some therapeutic options.
The loss of the Y chromosome with age increases the risk of aggressive bladder cancer
As men age, they lose the Y chromosome in some of their cells. This has been linked to an increased risk of developing certain diseases, including those listed below. cardiovascular.
The loss of the Y chromosome also occurs in different types of cancer, Among these are bladder cancers, although its impact or function is not fully defined. By reviewing the available clinical and genetic information of 300 men with bladder cancer, the team of researchers at Cedars-Sinai Hospital, led by Dan Theodorescu, found that those whose tumors showed a loss of the Y chromosome had a worse prognosis.
To investigate the effect of Y chromosome loss on bladder tumors, the team developed several mouse models of the disease. The researchers used bladder cancer cells that had naturally lost the Y chromosome, as well as cells from which the chromosome had been removed using CRISPR genome editing technology, and inoculated these into mice to generate tumors.
The analyses indicated that tumors derived from cells lacking a Y chromosome were more aggressive. Furthermore, these tumors had an altered T-cell-mediated immune response, making them more vulnerable to immunotherapy treatment.
“This study establishes, for the first time, a connection never before made between the loss of the Y chromosome and the immune system’s response to cancer,” said Dan Theodorescu. “We discovered that the loss of the Y chromosome allows bladder cancer cells to evade the immune system and grow very aggressively.” The researchers suggest that the loss of the Y chromosome could be an adaptive strategy used by tumor cells to avoid the immune system.
A gene expressed on the Y chromosome contributes to colon cancer metastasis
Colon cancer, the second leading cause of cancer death, is one of the types of cancer where the differences between the sexes are most pronounced. It is not only more common and aggressive in men, but it also spreads more readily to other tissues.
To better understand why these differences occur, a team of researchers at the MD Anderson Cancer Center, led by Ronald DePinho, generated different mouse models for colorectal cancer. These mice carried an oncogenic version of the gene. KRASor they had inactivated genes that are usually altered in patients with this type of cancer such as APC or certain tumor suppressor genes.
The team observed that male mice with KRASoncogenic individuals showed a higher frequency of metastasis and lower survival than females, differences that were not observed in the other models.
Using different approaches, the researchers found that the effect observed in mice KRASThis was due to the increased expression of the gene KDM5D. This gene, which is located on the Y chromosome, codes for an enzyme that regulates the expression of other genes by modifying histone proteins.
Through these epigenetic mechanisms, KDM5D represses the expression of a gene necessary for maintaining tissue integrity, thus facilitating the metastasis of tumor cells. Furthermore, it also inhibits the expression of genes involved in the immune system's detection and elimination of tumor cells. In this way, KDM5D not only facilitates metastasis but also "tricks" the immune system into not recognizing cancer cells.
Therapeutic implications of the results
Both studies suggest that the Y chromosome, essential for determining male biological sex, may play an important role in sex differences regarding cancer, with particular aggressiveness in men compared to women.
An interesting point is that in one study, the loss of the Y chromosome is linked to cancer aggressiveness, while in the other, it is the expression of a gene located on the Y chromosome. These results indicate that the tumor context, as well as the presence of other mutations such as KRAS, are also relevant.
Finally, both studies offer some approaches of therapeutic interest. For example, bladder tumors with Y chromosome loss are more susceptible to treatment with immune checkpoint inhibitors. And regarding colon cancer with mutations in KRAS, Strategies could be developed to modulate KDM5D activity. “These mechanistic results provide a framework for developing sex-specific precision medicine strategies for treating men with metastatic colon cancer,” the authors of the second study conclude.
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Fountain: https://genotipia.com/genetica_medica_news/el-cromosoma-y-influye-en-la-mayor-vulnerabilidad-de-los-hombres-al-cancer/
Scientific articles:
Abdel-Hafiz, H.A., Schafer, J.M., Chen, X. et al. And chromosome loss in cancer drives growth by evasion of adaptive immunity. Nature (2023). https://doi.org/10.1038/s41586-023-06234-x
Li, J., Lan, Z., Liao, W. et al. Histone demethylase KDM5D upregulation drives sex differences in colon cancer. Nature (2023). https://doi.org/10.1038/s41586-023-06254-7
Other sources:
Mutant KRAS regulates Y chromosome gene in colorectal cancer, driving metastasis and inhibiting anti-tumor immunity.
Loss of Y Chromosome in Men Enables Cancer to Grow
