A subset of X-chromosome genes seems to give females an extra degree of protection against cancer. This finding, which emerged from a study led by researchers at the Dana-Farber Cancer Institute and the Broad Institute of Harvard and MIT, is surprising because males also have an X chromosome, which might be expected to afford as much protection as the one unsilenced X chromosome in females. Yet some genes on the silenced X chromosome escape dormancy and function normally. These genes, it turns out, are crucial.

According to the researchers, fully functional tumor-suppressor genes on an otherwise idle X chromosome helps explain why females have a lower incidence of cancer than males. The researchers refer to such genes as EXITS, for escape from X-inactivation tumor-suppressor genes.

Details of the researchers’ work appeared November 21 in the journal Nature Genetics, in an article entitled, “Tumor-Suppressor Genes That Escape from X-Inactivation Contribute to Cancer Sex Bias.” The article describes how the researchers examined somatic alterations from more than 4100 cancers across 21 tumor types for sex bias.

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. 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 offline 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.

This finding prompted the scientists to consider whether KDM6A genes, and possibly other genes, are among the genes that can escape X inactivation. If so, the scientists reasoned, “good” copies of such genes could be sufficient to prevent cells from turning cancerous.

“Six of 783 non-pseudoautosomal region (PAR) X-chromosome genes (ATRX, CNKSR2, DDX3X, KDM5C, KDM6A, and MAGEC3) harbored loss-of-function mutations more frequently in males…in comparison to zero of 18,055 autosomal and PAR genes…,” wrote the authors of the Nature Genetics paper. “Male-biased mutations in genes that escape X-inactivation were observed in combined analysis across many cancers and in several individual tumor types, suggesting a generalized phenomenon.”

The authors concluded that “biallelic expression of EXITS genes in females explains a portion of the reduced cancer incidence in females as compared to males across a variety of 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 Dana-Farber’s Andrew Lane, M.D., Ph.D., a co-senior author of the Nature Genetics study along with Gad Getz, Ph.D., of the Broad Institute and Massachusetts General Hospital. “Data from the National Cancer Institute show that males carry about a 20% 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 cancer. The disparity is present among boys and girls, as well as men and women.

To explain the male/female disparities in cancer incidence, the scientists theorized that male cells would need a harmful mutation in only one copy of an EXITS gene to turn cancerous. Female cells, by contrast, would need mutations in both copies.

“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,” Dr. 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.”

One of the implications of the finding is that many cancers may arise through different molecular pathways in men and women. To circumvent the added genetic safeguards against cancer in female cells, tumors in women may employ alternate genetic circuits than in men.

To explore this possibility, the study authors recommend that future clinical studies of cancer treatments be “statistically powered”—that is, involve enough patients and tumor tissue samples—to understand whether men and women respond differently to treatment because of genetic differences in their tumors.

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