As a rule, humans have 23 pairs of chromosomes that contain the information necessary to keep them alive and that establish their physiological traits. One of these pairs determines the sex of each individual: females have two X chromosomes, and males have one X and one Y chromosome. This difference, which is behind the development of different sex organs and the variations they cause in the rest of the body, may explain, in part, why men tend to have a worse prognosis when they get cancer, and even why they tend not to live as long as women. Two articles published today in the journal Nature provide new information on the role of the male chromosome in vulnerability to various tumors.
One of these studies, led by Dan Theodorescu, director of oncology at Cedars-Sinai Hospital in Los Angeles, looked at what happens when cells lose the Y chromosome, something that happens in up to 40% of bladder tumors and is more frequent with the passage of time. First, the team collected data from 300 bladder cancer patients and observed a correlation between chromosome loss and a worse prognosis. Then, to try to prove that the absence explained the tumor’s aggressiveness, they used mouse cells. Tumors grew faster in those animals whose Y chromosome was missing, and a similar relationship was also seen in cells from which the Y had been removed by gene editing.
Next, the study’s authors put tumor cells in plaques which were not exposed to immune cells. These were injected into mice, some of which had been modified to have no T lymphocytes (responsible for controlling the rampant proliferation of cells that causes cancer), while others had operational lymphocytes. There was no difference in tumor growth in the presence or absence of the Y chromosome in the mice without immune cells, nor in the immunosuppressed culture. However, among healthy mice, the lack of the chromosome made the cancer much more aggressive. “These results tell us that when cells lose the Y chromosome, they deplete T lymphocytes, and without them to fight cancer, tumors grow aggressively,” Theodorescu says in a note from his institution.
The good news is that the Cedars-Sinai team’s results suggest that, in both mice and humans, the loss of the Y chromosome, in addition to making the tumors more aggressive, made them more vulnerable to a type of immunotherapy that restores the T lymphocytes’ ability to destroy the cancer. For Óscar Fernández-Capetillo, a researcher at the Spanish National Cancer Research Center (CNIO), the most interesting aspect of the study is its practical application. “The loss of the Y chromosome was known as a kind of marker, but it was not known how it affected tumor development. This group shows that tumor cells that lose the Y chromosome turn off the immune system that is going to destroy them, but they also see that these tumors respond better to immunotherapy,” he notes. “This work helps with the huge dilemma of identifying which patients are going to respond to immunotherapy,” he adds. However, he warns that “it is known that this effect exists, that the tumor with the missing Y chromosome responds to immunotherapy, but it is not known how much, and it will have to be studied.”
Juan Ramón González, a researcher at the Barcelona Institute for Global Health (ISGlobal) published an epidemiological study in 2020 with data from 9,000 men in which it was observed that the loss of function of six key genes of the Y chromosome increased the risk of developing cancer. “In the study published today, the link between the loss of the Y chromosome and immune system dysregulation in bladder cancer aggressiveness is reliably demonstrated. It is also observed that the loss of the Y chromosome is affected by methylation. In this line, we have seen that there are environmental factors that can have an influence, and other authors have shown that smokers, for example, have more Y chromosome loss. The therapeutic consequences of this work are immediate. By re-stimulating T cells through known interventions, it is possible to reduce the aggressiveness of the cancer,” explains Gonzalez. His team is now working with the company TruDiagnostics on finding similar biomarkers for women (on the X chromosome), who, when their extra X chromosome cup has activated incorrectly, also react worse to cancer. The authors of the Nature article also point to the existence of genes on the X chromosome related to those on the Y chromosome that may be of therapeutic interest.
In a second article that also appears in Nature today, a team led by Ronald De Pinho, from MD Anderson Cancer Center, in Houston, Texas, explains how they studied the influence of a gene on the Y chromosome on the increased severity of colon cancer in men. Using mice, they found that KRAS, a gene responsible for the transformation of normal cells into cancerous ones, increased the activity of the KDM5D gene on the male chromosome. This facilitated tumor progression and hindered its detection by the immune system. At a time when treatments for the multitude of cancers are expected to be almost individualized, work such as that published today in Nature helps experts to consider the different reactions of men and women to these diseases in order to better target diagnosis and treatment.
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