Why are Men More Likely Than Women to Develop Cancer Over the Course of Their Lives?

Statistics show that men have about a one in two chance of developing cancer during their lifetime, while women have a one in three chance. Why is men’s risk of the disease higher?

A variety of factors may account for this difference. Historically, men were heavier smokers than women, leading to more lung, head and neck, esophageal, and bladder cancers. In addition, large numbers of men are found to have prostate cancer, although most cases are not dangerous. The number of cases of cervical cancer has declined drastically in the past 75 years, as a result of several trends, including improved and more frequent screening methods like Pap tests, which can detect changes in the cervix before cancer develops.

In research led by scientists at Dana-Farber, the Broad Institute of MIT and Harvard, and Massachusetts General Hospital (MGH), investigators uncovered a genetic explanation for the disparity.

Females, it turns out, carry an extra copy of certain protective genes in their cells, which functions as an additional line of defense against cells’ growing out of control, investigators found. Though not solely responsible for cancer’s apparent “bias” toward males, the duplicate copies likely account for some of the imbalance, including up to 80 percent of the excess male cases in some tumor types.

“Across virtually every type of cancer, occurrence rates are higher in males than in females. In some cases, the difference might be very small – just a few percent – but in certain cancers, incidence is two or three times higher in males,” said Andrew Lane, MD, PhD, of Dana-Farber, the co-senior author of the study with Gad Getz, PhD, of MGH and the Broad Institute. “Data from the National Cancer Institute show that males carry about a 20 percent higher risk than females of developing cancer. That translates into 150,000 additional new cases of cancer in men every year.”

X marks the spot

Previous research found that in one form of leukemia, the cancer cells often carried a mutation in a gene called KDM6A, located on the X chromosome – one of the sex chromosomes that determine whether an individual is male or female. (Females cells carry two X chromosomes, while males carry one X chromosome and a shorter, smaller Y chromosome.) If KDM6A is a tumor-suppressor gene – responsible for preventing cell division from spinning out of control – the mutation could lead to cancer by crippling that restraint system.

Andrew Lane, MD, PhD, and David M. Weinstock, MD.
Andrew Lane, MD, PhD, and David M. Weinstock, MD.

One then might expect female cells to be just as vulnerable to this gene mutation. During embryo formation, one of the X chromosomes in female cells shuts down and remains off-line for life. A mutation in KDM6A on the active X chromosome, therefore, should lead to the same cell-division havoc as it does in males. Unexpectedly, however, researchers detected KDM6A mutations more often in male cancers. It turns out that that some genes on the inactivated X chromosome in female cells “escape” that dormant state and function normally. One of those awakened genes happens to be a working copy of KDM6A. The “good” copy of the gene is sufficient to prevent the cell from turning cancerous.

The study, whose co-lead authors are Andrew Dunford, of the Broad Institute and David M. Weinstock, MD, of Dana-Farber and the Broad Institute,  explored whether this phenomenon – the presence of fully functional tumor-suppressor genes on an otherwise idle X chromosome – underlies the broader phenomenon of cancer’s partiality toward male cells. The researchers dubbed such genes “EXITS,” for Escape from X-Inactivation Tumor Suppressors.

“Under this theory, one of the reasons cancer is more common in males is that male cells would need a harmful mutation in only one copy of an EXITS gene to turn cancerous,” Lane said. “Female cells, by contrast, would need mutations in both copies.”

To test this hypothesis, researchers at the Broad Institute scanned the genomes of more than 4,000 tumor samples, representing 21 different types of cancer, looking for various types of abnormalities, including mutations. They then examined whether any of the irregularities they found were more common in male cells or female cells.

The results were striking. Of nearly 800 genes found solely on the X chromosome, six were more frequently mutated – and incapacitated – in males than females. Of more than 18,000 other genes, none showed a gender imbalance in mutation rates.

Of the six genes more likely to be mutated in males, five were known to escape X chromosome inactivation, making them strong candidates to be EXITS genes.

“The fact that the very genes which are more often mutated in males are found exclusively on the X chromosome – and that several of them are known to be tumor-suppressors and escape X-inactivation – is compelling evidence of our theory,” Lane remarked. “The protection afforded by the working copies of these genes in female cells may help explain the lower incidence of many cancers in women and girls.”

Even as this research sheds light on why cancer is more common in males, scientists are still working to understand the reasons for other types of cancer disparities, such as those involving race.