Two studies published in Nature journal have shed light on the crucial role the Y chromosome may play in understanding why men often suffer more severe outcomes from cancer than women.
The Y chromosome triggers male development in most species of mammals.
The first of these studies was led by Dr Ronald DePinho, of the MD Anderson Cancer Centre in Houston, Texas, focused on colorectal cancer – the second deadliest type of cancer worldwide.
This cancer type is known to be more frequent, aggressive, and metastatic in males.
Using a mouse model driven by a known oncogene – a gene that has the potential to cause cancer – called Kras, Dr DePinho and his team noticed a striking similarity with humans.
“In male mice, we observed a higher frequency of metastasis and worse survival, mirroring the outcomes seen in humans,” Dr DePinho told The National.
An unregulated gene on the Y chromosome appeared to be the culprit.
“This gene plays a part in driving tumour invasion and immune escape, providing a potential explanation for sex-specific differences in the progression of Kras-driven colorectal cancer,” Dr DePinho added.
“We identified a gene on the Y chromosome that makes colorectal cancer more aggressive in males. This gene influences others involved in the ability of cancer cells to spread and to evade the immune system.”
In a separate study, Dr Dan Theodorescu, director of the Samuel Oschin Comprehensive Cancer Institute at the Cedars-Sinai Medical Centre in Los Angeles, and his team investigated the implications of losing the Y chromosome – a phenomenon observed in various cancer types.
They found that bladder cancers lacking the Y chromosome were more aggressive and exhibited a dampened T cell-mediated immune response.
T cells are part of the immune system, developing from stem cells in the bone marrow. These help protect the body from infection and may help fight cancer.
In a study of 300 male bladder cancer patients, Y chromosome loss was associated with a poorer prognosis.
Dr DePinho, while not involved in this bladder cancer study, offered his interpretation to The National.
“The Y chromosome can play different roles across different cancer types, and understanding the implications of its loss can be challenging due to the many genes it carries,” he said.
These studies offer potential strategies for developing therapies specifically tailored for men.
“Male colorectal cancer patients, especially those with Kras mutations, may require more proactive measures to prevent metastasis,” Dr DePinho suggested.
“Standard immune therapies may not work as well in these men due to the cancer cells' ability to evade the immune system.”
When discussing the implications of their findings on immune evasion, Dr DePinho said: “Males with Kras-mutant colorectal cancer might need drugs that neutralise the repressive functions of the identified Y chromosome gene, KDM5D, for successful immune therapies.”
He offered reassurance regarding possible the risk or limitations of therapies targeting the Y chromosome, including the use of histone deacetylase inhibitors – a relatively new class of anti-cancer agents.
“We do not anticipate any untoward effects caused by neutralising KDM5D,” Dr DePinho said.
“Moreover, histone deacetylase inhibitors – a potential component of such therapies – are already deemed sufficiently safe for patient use.”
He said these revelations underline the significance of the Y chromosome in understanding of sex-specific differences in cancer progression and treatment.
These insights could guide future research, leading to more effective, personalised cancer treatments for men.
