differences have been observed in deadly brain tumors, such as
affects the differential susceptibility, response to treatment, and
survival in male and female glioblastoma patients
of new treatments tailored to treat specific subtypes of glioblastoma
could improve survival of patients
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
, a publication of the American Association for the
Advancement of Science (AAAS).
‘Deadly brain tumors such as glioblastomas exhibit sex-specific differences. Males are more susceptible to these tumors than females. Moreover, females respond better to treatment than males and their survival rate is also higher.’
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
What is Glioblastoma?
known as glioblastoma multiforme (GBM), is a fast-growing, highly malignant
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.
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.
What Did the Study Involve?
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
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
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.
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
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.
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.
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
- Males in one of the clusters survived longer than the other
four clusters - 1.5 years vs. 1
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.
"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
"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
the Cleveland Clinic, Case Western Reserve University and TGen, a genomics
research institute, also contributed to the research.
- Sex differences in GBM revealed by analysis of patient imaging, transcriptome, and survival data - (http://stm.sciencemag.org/content/11/473/eaao5253)