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Study reveals genetic explanation for cancer’s higher incidence in males than females

In a new study, a group of Boston scientists, including researchers at Dana-Farber Cancer Institute, offer a genetic explanation for the age-old conundrum of why cancer is more common in males than females.

Females, it turns out, carry an extra copy of certain protective genes in their cells – an additional line of defense against the cells growing out of control – the investigators report in a paper published online by Nature Genetics. Though not solely responsible for cancer’s “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, report the study authors, based at Dana-Farber, the Broad Institute of Harvard and MIT, and Massachusetts General Hospital.

“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 the Broad Institute and Massachusetts General Hospital. “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.”

Despite the size of the gap, the reasons for this divergence have been difficult to discern. The historic explanation – that men were more likely to smoke cigarettes and be exposed to hazardous chemicals in the work environment – has proven inadequate, because even as smoking rates have dropped and occupational patterns changed, men still outpace women in developing many cancers, including some associated with tobacco use such as kidney, renal, bladder, and oral cancers, Lane said. The disparity is present among boys and girls, as well as men and women.

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; males carry an 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.

One might expect female cells to be just as vulnerable to the 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, KDM6A mutations were detected more often in male cancers. It turns out 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.