Men have more cancer than women. Throughout their lives, one in two men and one in three women will have cancer, according to the Spanish Society of Medical Oncology. By 2040, the incidence of the estimated number of new cases in them is close to 14.5 million a year, while in them it is closer to 12.5 million, as warned by the Global Cancer Observatory. In addition, mortality is higher in males.
The causes of these differences are not clear. Until now, it had been believed that it was due to lifestyle; that since some risk factors such as tobacco and alcohol consumption predominate in them, cancers are more prevalent and more aggressive. But scientists have already called that hypothesis into question, and researchers are clear that there must be something beyond habits. Something, perhaps, that has to do directly with the male sex chromosome.
Now, two independent investigations that are published in the journal Nature suggest that the cause may lie in that structure, specifically in the Y chromosome (women have two X and men XY), and not in social or behavioral differences related to smoking, alcohol consumption, a greater consumption of red meat or the influence of hormones. Both works indicate that this structure that determines the sex of each person, explains why men tend to have a worse prognosis for cancer.
The first investigation focuses on the aggressive bladder cancer, since men are approximately twice as likely to die from this tumor. Led by Dan Theodorescu, director of the oncology area at Cedars-Sinai Hospital in Los Angeles (USA), it has observed what happens when cells lose the Y chromosomea situation that occurs in up to 40% of bladder tumors.
The scientists carried out their study in cells from laboratory mice and with data from 300 human patients with bladder cancer, and concluded that losing the Y chromosome helps the cancer cells evade the immune system of the organism. “This study demonstrates for the first time a never-before-established connection between Y-chromosome loss and the immune system’s response to cancer,” says Theodorescu.
The key, it seems, lies in T cells, a type of white blood cell that is part of the immune system and helps protect the body from infection and fights cancer. “When cells lose the Y chromosome, they run out of T cells. No T cells to fight cancerthe tumor grows more aggressively,” adds the author of the study.
In both mice and humans, the loss of the Y chromosome made the tumors more aggressive. But, on the other hand, they also discovered that made them more vulnerable to a type of immunotherapy that restores the ability of T lymphocytes to destroy cancer. This is a very positive finding that could have medical applications and, according to Theodorescu, opens the door to determine which patients could benefit from existing immunotherapies.
But Why does the Y chromosome disappear? It seems proven that the most determining factor is age. As they age, some men’s cells tend to lose it completely. Added to this condition are other environmental factors or habits such as smoking that could be associated, but there is still research ahead to prove it.
It is curious: already in 2020, a Spaniard, Juan Ramón González, a researcher at the Barcelona Institute for Global Health (ISGlobal), published a study that associated the loss of function of six key genes on the Y chromosome with increased risk of developing cancer. Today this new evidence is added, with which it seems to confirm what Spanish research has already drawn: that there is a link between the loss of the Y chromosome and deregulation of the immune system.
In the same line, the other research published on the matter is published in Nature, in this case, focused on colon cancer. Thus, researchers from the MD Anderson Cancer Center of the University of Texas claim to have discovered a gene on the Y chromosome associated with this tumor, which is the most diagnosed in Spain in both sexes, although in men it tends to have a worse prognosis.
According to the study, which only has preclinical results, this is due to a gene located on the Y chromosome, the KDM5D. Led by researcher Ronald DePinho, the authors used a mouse model with colorectal cancer caused by the mutation of an oncogene called KRAS, which is more frequent, aggressive and metastatic in men.
The researchers observed a higher frequency of metastasis and poorer survival in male mice, identifying this gene as the cause of cancer cells increasing their ability to spread and avoiding detection by the immune system. We could say that KDM5D is a “helper” of cancer cells.
In any case, more research will be needed to better understand why men and women react differently to cancer diseases.