A team of researchers led by Washington University School of Medicine in St. Louis has identified distinct molecular signatures of glioblastoma in men and women. This suggests that tailoring treatments to men and women with glioblastoma based on the molecular subtypes of their tumors may improve survival for all patients.

Culling patient MRI scans and survival data from a cancer research database, the researchers calculated tumor growth velocity every two months for the duration of therapy in 63 glioblastoma patients, 40 males and 23 females who received standard chemo-radiation treatment following surgery. While initial tumor growth velocities were similar between females and males, only the females showed a steady and significant decline in tumor growth after treatment with temozolomide, the most common chemotherapy drug used to treat glioblastoma.

“The males did not respond as well, and we wanted to understand why, so we looked at the underlying genetics of patients’ tumors,”

said Joshua B. Rubin, a Washington University professor of pediatrics and of neuroscience and the study’s co-senior author.

The researchers tapped into The Cancer Genome Atlas (TCGA), and applied sophisticated statistical algorithms to distinguish male- or female-specific gene expression patterns from such patterns that were shared among the male and female patients. They then focused on the sex-specific gene expression to identify molecular subtypes that corresponded to differences in survival for males and for females.

“We observed tremendous genetic sex differences in the tumors of glioblastoma patients that correlated with survival,”

said study’s co-senior author Jingqin “Rosy” Luo, a Washington University associate professor of surgery in the Division of Public Health Sciences.

Specifically, the researchers showed that the tumors of patients with glioblastoma cluster into 10 distinct subtypes: five for tumors in males and five for tumors in females. The clusters are distinguished by gene activity and survival.

The researchers validated the clusters in three additional data sets and also showed that even genes activated at similar levels in tumors in males and females can result in substantial sex-specific effects on survival.

“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,”

Rubin said. “This tells us it might be better to separate males and females and examine their sex-specific genetic signatures.”

Among diseases in general, sex differences are often tied to hormones. For example, the female hormone estrogen contributes significantly to more women getting breast cancer than men. However, with glioblastoma diagnosis and survival, sex hormones did not directly contribute to female and male differences, Rubin said. “The sex-specific genetic activity in glioblastoma is not dependent on the acute actions of circulating sex hormones as differences are evident across all stages of life.”

“In a broader sense, I want our research to encourage people to think more about how diseases uniquely affect males and females, making it the norm and not the exception,”

Rubin added. “I hope the research will inspire more specific approaches to treatments. It may be that we shouldn’t be using the same criteria when treating diseases in males and females.”
The findings were published on Jan. 2 in Science Translational Medicine. Enditem

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