Erin O’Donnell, Harvard Magazine
Oncologists know that men are more prone to cancer than women; one in two men will develop some form of the disease in a lifetime, compared with one in three women.But until recently, scientists have been unable to pinpoint why. In the past, they theorized that men were more likely than women to encounter carcinogens through factors such as cigarette smoking and factory work. Yet the ratio of men with cancer to women with cancer remained largely unchanged across time, even as women began to smoke and enter the workforce in greater numbers.
Pediatric cancer specialists also noted a similar “male bias to cancer” among babies and very young children with leukemia. “It’s not simply exposures over a lifetime,” explains Andrew Lane, assistant professor of medicine and a researcher at the Dana-Farber Cancer Institute. “It’s something intrinsic in the male and female system.” Now, discoveries by Lane and the Broad Institute of Harvard and MIT reveal that genetic differences between males and females may account for some of the imbalance. A physician-researcher who studies the genetics of leukemia and potential treatments, Lane says that he and others noted that men with certain types of leukemia often possess mutations on genes located on the X chromosome. These mutations damage tumor-suppressor genes, which normally halt the rampant cell division that triggers cancer.
Lane initially reasoned that females, who have two X chromosomes, would be less prone to these cancers because they have two copies of each tumor suppressor gene. In contrast, men have an X and a Y chromosome—or just one copy of the protective genes, which could be “taken out” by mutation. But the problem with that hypothesis, Lane says, was a “fascinating phenomenon from basic undergraduate biology called X-inactivation.” In a female embryo, he explains, cells randomly inactivate one of the two X chromosomes. “When a female cell divides, it remembers which X chromosome is shut down, and it keeps it shut down for all of its progeny.” If female cells have only one X chromosome working at a time, then they should be just as likely as male cells to experience cancer-causing gene mutations.
So Lane and his team dug deeper into existing studies and encountered a little-known and surprising finding: “There are about 800 genes on the X chromosome,” he says, “and for reasons that are still unclear, about 50 genes on that inactive X chromosome stay on.” In a “big Aha! moment,” Lane’s group realized that those gene mutations common in men with leukemia were located on genes that continue to function on women’s inactive chromosome. The researchers dubbed those genes EXITS for “Escape from X-Inactivation Tumor Suppressors.” Women, Lane explains, thus have some relative protection against cancer cells becoming cancer because they, unlike men, do have two copies of these tumor-suppressor genes functioning at all times.