The deadliest and most common type of brain cancer occurs roughly twice as often in men than it does in women, and leads to more serious complications in a much shorter amount of time. Science has long wondered why, and a new study from Washington University School of Medicine in St. Louis suggests the answer could lie in a single gene.
Glioblastoma multiforme, the most common of the malignant primary brain tumors, increases each year by roughly two to three cases per 100,000 people. Most people don’t live much longer than 15 months, and the five-year survival rate hovers around four percent. For much of the time science has researched these tumors, genetic mutation has been proposed as a cause. The latest study upholds this theory, claiming men produce far less of the retinoblastoma protein (Rb), which helps the body suppress tumor growth.
"This is the first time anyone ever has identified a sex-linked difference that affects tumor risk and is intrinsic to cells, and that's very exciting," said senior author of the study Dr. Joshua Rubin in a statement.
Rubin and his colleagues used cell cultures to test the hypothesis that Rb deficiencies in men could underlie their increased risks. The team made a few genetic alterations and exposed the culture to a growth factor, in order to simulate the presence of glioblastoma, and ultimately found the male cells turned cancerous much faster and to a greater degree than the female cells.
Further driving the finding home, they found depleting the female cells of Rb started producing the same effect as the male cells. This point was particularly insightful because it meant the RB gene was working in isolation in their model (though not necessarily as the only factor overall). It also means other cancers that carry sex-dependent risks, such as some liver cancers, may rely on tumor-suppressing proteins.
"Knowing more about why cancer rates differ between males and females will help us understand basic mechanisms in cancer, seek more effective therapies, and perform more informative clinical trials,” said Rubin, an associate professor in neurology and pediatrics.
Part of the decision to screen for RB came from glioblastoma’s natural properties. For instance, prior research has already shown the risks for children don’t stray too far from adult gender lines. And the same goes for middle-aged women. So puberty and menopause, regulated by specific sex hormones, can’t be playing a role, Rubin asserts. There had to be some other mechanism driving the sex-specific differences.
With this knowledge, the team hopes to use the gene in clinical trials that evaluate the safety and efficacy of certain drug therapies. Rb, the protein, stems from activation of the gene, RB, which means if researchers can find a pharmaceutical way to trigger the gene, brain cancer patients would, in theory, live longer.
"These results suggest we need to go back and look at multiple pathways linked to cancer, checking for sex differences,” Rubin said. “Sex-based distinctions at the level of the cell may not only influence cancer risk but also the effectiveness of treatments."
Source: Sun T, Warrington NM, Luo J, et al. Sexually dimorphic RB inactivation underlies mesenchymal glioblastoma prevalence in males. The Journal of Clinical Investigation. 2014.