Study Finds EXITS Gene Mutations May Contribute to Cancer Sex Bias
According to Surveillance, Epidemiology, and end Results (SEER) data from 2008 to 2012, American males have an excess risk of 20.4% of developing any cancer compared with females, and there is a ≥ 2:1 male predominance for some individual cancers. This excess risk results in approximately 153,000 new additional cases of cancer in men every year.
A study by Dunford et al investigating the unexplained predominance of cancer incidence in males vs females has found the biallelic expression of escape from X-inactivation tumor suppressor (EXITS) genes in females may account for a portion of the reduced cancer incidence in females across a variety of tumor types. Clinical studies are needed to understand the sex-specific differences in outcomes resulting from distinct tumor genetics, according to the study authors. The study was published in Nature Genetics.
Study Methodology
The researchers hypothesized that mutations in tumor suppressor genes that escape X inactivation could underlie a substantial fraction of excess male cancers, because males would require only a single deleterious mutation, whereas females would require two. The researchers termed these genes EXITS for “escape from X-inactivation tumor suppressors.”
To test the hypothesis, the researchers scanned the genomes of more than 4,000 tumor samples, representing 21 different types of cancer, for sex bias.
Study Results
The researchers found that of the nearly 800 genes found solely on the X chromosome, 6—ATRX, CNKSR2, DDX3X, KDM5C, KDM6A, and MAGEC3—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.
“We conclude 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,” said the study authors.
Study Implications
“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-activation—is compelling evidence of our theory,” said Andrew A. Lane, MD, PhD, Assistant Professor of Medicine at Harvard Medical School and Assistant Professor of Medical Oncology at Dana-Farber Cancer Institute and a coauthor of this study, in a statement. “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.”
Andrew A. Lane, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, is the corresponding author of this article in Nature Genetics.
Funding for this study was provided by the National Cancer Institute, an American Society of Hematology Scholar Award, a V Foundation Scholar Award, and a Stand Up to Cancer Innovative Research Grant.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
