New Sex-Specific Genetic Risk Factors Identified in Brain Cancer

The potential differences in the genetic risk factors among men and women for developing glioma may shed light on a new way to assess such risks, according to a meta-analysis published in Scientific Reports.

The prevalence of gliomas in men — which comprise about 80 percent of all malignant brain tumors – is known among the scientific community. But while these tumors are 50 percent more common in males than in females, not much research exists on what role sex-based genetic differences play in the risk of developing a glioma.

Therefore, researchers from Case Western Reserve University School of Medicine, in collaboration with a group of international researchers, conducted a meta-analysis using sex-stratified logistic regression models to analyze data from 4,831 male and 3,206 female glioma, glioblastoma only and non-glioblastoma patients.

The consortium included more than 35 researchers from over 30 international institutions, universities and government agencies.

In an interview with CURE, Quinn Ostrom, Ph.D., MPH, postdoctoral associate at the Baylor College of Medicine, and Jill Barnholtz-Sloan, Ph.D., a Sally S. Morley Designated Professor in Brain Tumor Research at the Case Western Reserve University School of Medicine, explained their research further.

According to Ostrom and Barnholtz-Sloan, this analysis “takes a set of individuals with a disease (in this case glioma) and a set of individuals without cancer, and compares individual letters in their DNA (whether they have an A, C, T or G) at millions of locations across the genome to see if there are any differences that may be associated with glioma.”

As anticipated, the scientists discovered that men and women do indeed have genetic differences. Ostrom and Barnholtz-Sloan noted three major findings in particular.

“Two genes were found to have differences between males and females that had previously been identified when males and females were analyzed together,” the doctors explained. “One of these, near the gene EGFR, was estimated to have a larger effect in males. The other, near the gene CCDC26, was estimated to have a larger effect in females.”

The third finding, a new association that was identified in females only near gene DAG1, was particularly surprising. According to Barnholtz-Sloan, this genetic region does have associations for a variety of other traits including autoimmune diseases, but had not previously been associated with gliomas.

The researchers also noted that the genetic associations discovered have a relatively small influence on the overall lifetime risk of developing a glioma, which is around 1 percent.

“Each of these factors only contributes a small proportion of risk to individuals who have these alleles. Having one copy of the risk allele near EGFR increases risk by 33 percent in males, which would increase risk to roughly 1.33 percent. The newly identified (gene) associated near DAG1 increases risk by 22 percent in females, which would increase lifetime risk to roughly 1.22 percent.”

As for what implications these findings have on the future, Barnholtz-Sloan explained that the results from this study could be used to build a customized genetic testing panel for males versus females to assess risk of glioma.

“However, since there still may be other risk factors we have not yet discovered, I am not sure how long a test like this would take to be used in the clinic,” she added.