Gender Differences Exist in Brain Tumors

It has long been observed that males are more susceptible to cancer than females. This occurs in many types of cancer, including cancers of the brain, such as glioblastoma. However, why these differences are observed between men and women was unknown, until now. A group of researchers at the Washington University School of Medicine, St. Louis, USA have found distinct molecular signatures that explain this disparity in men and women suffering from glioblastoma. The researchers predict that if the treatment of these patients can be tailored according to the subtype of the glioblastoma, it will likely improve the survival and overall prognosis. The study has been published in Science Translational Medicine, a publication of the American Association for the Advancement of Science (AAAS).

The study was led by Dr. Joshua B. Rubin, MD, PhD, who is a Professor of Pediatrics, Oncology and Neuroscience at Washington University School of Medicine, St. Louis, Missouri, USA. He is also the co-founder of the Pediatric Neuro-Oncology Program at St. Louis Children’s Hospital and one of the co-senior authors of the study. He indicated that the study is likely to have an immediate impact on the management of glioblastoma patients. The research findings indicate that glioblastoma patients should be stratified according to sex and the efficacy and response to therapy should be evaluated in a sex-specific manner. He stressed that although sex-specific differences have a direct impact on medical treatment; this aspect is often overlooked while designing personalized therapies.

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What is Glioblastoma?

Glioblastoma, also known as glioblastoma multiforme (GBM), is a fast-growing, highly malignant brain tumor that originates from star-shaped glial cells known as astrocytes and oligodendrocytes, which provide support and protection to the nerve cells and maintain homeostasis in the brain. Due to the highly invasive and aggressive nature of glioblastomas, they are often referred to as grade IV astrocytomas.

Glioblastomas commonly occur in the cerebral hemispheres, particularly in the frontal and temporal lobes. Symptoms include headaches, seizures, drowsiness, nausea, vomiting, blurred vision, and personality changes. Glioblastomas are twice as prevalent in males as in females and are usually diagnosed over the age of 50 years. Treatment involves surgery, followed by chemotherapy and radiotherapy. Despite these aggressive treatment approaches, cancer stem cells often survive and rapidly divide to replace the killed cancer cells, as a result of which recurrence can occur within six months. This is the most devastating brain cancer and often results in death within 15 months of diagnosis.

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What Did the Study Involve?

The researchers observed that while treating glioblastoma patients, the women responded better than men. In order to understand these sex differences in response to therapy the researchers looked into the following two aspects:

• Tumor growth velocity
• Sex-specific gene expression

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Tumor Growth Velocity

Dr. Kristin R. Swanson, PhD, who is a mathematical oncologist at the Mayo Clinic, Phoenix, Arizona, USA, calculated the tumor growth velocity by examining brain MRI scans of glioblastoma patients. The tumor growth velocity is calculated while the patients are undergoing anticancer treatment in order to establish how well the tumors are responding to therapy. This also sheds light on whether the drugs being administered are really helping the patients.

Procedure: The researchers used brain MRI scans and survival data of patients from a cancer research database to determine the tumor growth velocity in 63 glioblastoma patients (40 males and 23 females). The patients received standard chemo-radiation therapy, following surgery.

Results: Initially, there was no difference between the males and females. However, the females showed a steady and significant reduction in tumor growth following treatment with temozolomide, which is a first-line drug for the treatment of glioblastoma. In order to understand why the males didn’t respond well to therapy, the researchers decided to look at the sex-specific gene expression in the patients.

Sex-specific Gene Expression

The researchers culled data from The Cancer Genome Atlas (TCGA), a program launched in 2005 to study the genetic basis of cancer and funded by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), under the National Institutes Health (NIH), USA.

This part of the study was led by Dr. Jingqin Luo, PhD, an Assistant Professor of Surgery at the Division of Public Health Sciences, Institute for Public Health, Washington University, St. Louis and the study’s co-senior author. The data was analyzed by the study’s lead author, Dr. Wei Yang, PhD, who is a bioinformatics specialist in the Department of Genetics, Washington University, St. Louis.

Procedure: The researchers used sophisticated statistical algorithms to differentiate between the male- vs. female-specific gene expression patterns that were observed in male and female glioblastoma patients. The team then studied the sex-specific gene expression to find molecular subtypes of glioblastoma that impacted the differential survival of males and females.

Results: There were huge genetic differences in tumors of glioblastoma patients, which strongly correlated with survival. The researchers showed that the glioblastomas were clustered into ten distinct subtypes, which included five tumor subtypes for males and five for females. The clusters could be differentiated by gene activity and survival. For example:

• Females in one of the clusters survived longer than the other four clusters – 3 years vs. 1 year
• Males in one of the clusters survived longer than the other four clusters – 1.5 years vs. 1 year

The clusters were validated in three additional datasets. It was seen that even genes that were activated at equal magnitudes in tumors of males and females, exhibited significant sex-specific effects on survival.

Expert Comments

“Additionally, 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. 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.”

“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, and as a next step we should definitely develop and evaluate sex-specific treatment regimens for glioblastoma.”

Scientists from the Cleveland Clinic, Case Western Reserve University and TGen, a genomics research institute, also contributed to the research.

Reference:

1. Sex differences in GBM revealed by analysis of patient imaging, transcriptome, and survival data - (http://stm.sciencemag.org/content/11/473/eaao5253)

Source-Medindia