Genetic differences may explain cancer happening more to men

Doctors have puzzled over the stats for years: Cancer strikes 1 in 2 men vs. just 1 in 3 women. Even among babies and children with leukemia, boys are more likely to develop the disease than girls.

“Why Is Cancer More Common in Men?,” by Erin O’Donnell in Harvard Magazine’s March/April 2017 issue, reveals that researchers may finally be able to answer that question.

The article focuses on the work of Andrew Lane, a physician and researcher at the Dana-Farber Cancer Institute who specializes in the genetics of leukemia.

Lane got interested in what’s up with the X chromosome. On a normal one, there are tumor-suppressor genes that nip excessive cell division in the bud. So if you have a mutation that affects these genes, that can be bad news. (For you, anyway. It’s great news for cancer.) And it seems like especially bad news for guys, who have only one X chromosome. Women, who are born with a pair of X chromosomes — and therefore, two versions of those tumor-suppressor genes would seem to have a builtin safety net.

But not so fast, explains Lane, invoking a phenomenon called “X-inactivation.” In women, one X chromosome is randomly shut down, and it stays kaput. There goes that advantage, right?

Except, wrong! “There are about 800 genes on the X chromosome,” Lane tells O’Donnell, “and for reasons that are still unclear, about 50 genes on that inactive X chromosome stay on.” So here’s the kicker: The gene mutations common in men with leukemia match up with the genes that inexplicably stay on in women. (The researchers named those genes EXITS, as in “Escape from X-Inactivation Tumor Suppressors.”) That means women really do have a backup version to use in case of emergency.

For the next step in this research, Lane partnered with the Broad Institute of Harvard and MIT. Their collective goal? “To comb through gene-sequencing data for more than 4,000 tumors that included 21 different cancers,” O’Donnell writes. In findings published last fall in Nature Genetics, they announced more-clear connections between gene mutations in men and the active genes on women’s inactive chromosome.

The upshot of these findings, Lane says, is that researchers can’t ignore the differences between men and women. Basically, they need an EXITS strategy.