A team of researchers led by Washington University School of Medicine have identified distinct molecular signatures in cancers like the deadly brain tumor glioblastoma in male and female patients. These unique molecular signatures can explain why more males are diagnosed with and die from cancer compared to women.
Furthermore, these findings, published January 2nd in Science Translational Medicine, could be used to better treat both men and women with glioblastoma and increase chances of survival.
“It is our expectation that this study could have an immediate impact on the care of patients with glioblastoma and further research, as the findings indicate we should be stratifying male and female glioblastoma into risk groups and evaluating the effectiveness of treatment in a sex-specific manner,” the study’s co-senior author, Joshua B. Rubin, MD, PhD, a Washington University professor of pediatrics and of neuroscience, said. “The biology of sex differences and its applications in medicine are highly relevant but almost always ignored aspects of personalized treatments.”
The researchers realized that standard glioblastoma treatment is often more effective in women than in men. Using MRI scans and patient data from a cancer research database, the team measured velocity growth of tumors every two months in 40 males and 23 females with glioblastoma. They noticed that tumor size steadily shrunk in females who took the chemotherapy drug, temozolomide, whereas the males’ tumors seemed unaffected.
“The males did not respond as well, and we wanted to understand why, so we looked at the underlying genetics of patients’ tumors,” Rubin said.
Using the The Cancer Genome Atlas (TCGA), a National Cancer Institute- and National Human Genome Research Institute-funded project launched in 2005 to find the genetic basis of cancer, the researchers employed statistical algorithms to differentiate male- or female-specific gene expression patterns from male- and female-shared patterns. They then focused in on the sex-specific gene expression to find the molecular subtypes that were linked to survival in males and females.
“We observed tremendous genetic sex differences in the tumors of glioblastoma patients that correlated with survival,” the study’s co-senior author Jingqin “Rosy” Luo, PhD, a Washington University associate professor of surgery in the Division of Public Health Sciences. “All evidence supports the need to define these distinctions and incorporate the sex differences into glioblastoma biology research and treatment.”
“We identified genetic pathways that correlated with the longest survival, and they were very different in males compared with females,” Rubin said. “For example, in males survival was all about regulating cell division, which suggests that drugs that block cell-cycle progression may be more effective in men. For females, survival was all about regulating invasiveness, which suggests that drugs targeting integrin signaling may be more effective in women.”
“This tells us it might be better to separate males and females and examine their sex-specific genetic signatures,” he continued. “We tested this hypothesis by doing a series of in vitro drug screens in which we took four relatively common chemo drugs and looked at how the expression of these genes correlated with response to those drugs. In both males and females, there was a clear correlation.”
And unlike other sex-linked diseases, glioblastoma is not related to hormones like breast cancer is linked to estrogen.
Rubin says that he wants the findings of this study to encourage more people to consider sex in relation to disease treatment.
“I hope the research will inspire more specific approaches to treatments,” he said. “It may be that we shouldn’t be using the same criteria when treating diseases in males and females, and as a next step we should definitely develop and evaluate sex-specific treatment regimens for glioblastoma.”