Pilocytic astrocytoma can affect any brain region (image: Wikimedia Commons)

New biomarkers help brain tumor assessment
2015-09-23

Brazilian researchers have identified gene alterations that could help predict outcomes for patients with pilocytic astrocytoma, one of the most frequent brain tumors in children.

New biomarkers help brain tumor assessment

Brazilian researchers have identified gene alterations that could help predict outcomes for patients with pilocytic astrocytoma, one of the most frequent brain tumors in children.

2015-09-23

Pilocytic astrocytoma can affect any brain region (image: Wikimedia Commons)

 

By Karina Toledo

Agência FAPESP – Brazilian researchers have identified alterations in the BRAF and FGFR1 genes that may help physicians with prognostic evaluation and treatment planning for patients suffering from pilocytic astrocytoma, one of the most frequent brain tumors in children.

Their findings, which are part of a research project supported by FAPESP, were published in July in the Journal of Neuropathology and Experimental Neurology. According to the authors, the discovery could also pave the way to a new type of therapy.

“Pilocytic astrocytoma is a benign tumor in most cases, but 20% of patients develop complications. Until now, there hasn’t been a way of identifying patients who genuinely need more aggressive treatment, and any brain intervention, however minimal, can have a major impact,” said Rui Manuel Reis, Head of Science at the Barretos Cancer Hospital’s Diagnostic Center in São Paulo State, Brazil.

Any brain region can be affected by pilocytic astrocytoma, which occurs mainly in children and young adults, according to Reis. It used to be attributed to disorderly growth of astrocytes, star-shaped glial cells in the brain and spinal cord that physically support and nourish neurons, but the predominant hypothesis today is that it can arise from stem cells that are precursors of neurons and oligodendrocytes as well as astrocytes.

“Although brain tumors are less frequent in children than hematologic neoplasms, they’re the leading cause of death from cancer,” he said. “This is because knowledge and hence treatment of lymphoma and leukemia have advanced significantly in recent years. That hasn’t been the case for brain tumors.”

Recent studies suggest alterations in BRAF and FGFR1 may be associated with the development of pilocytic astrocytoma, the most common type of pediatric brain tumor, according to Reis.

To investigate the frequency of these genetic anomalies in the Brazilian population and whether they influence the progression of brain cancer, the Barretos group evaluated tumors taken from 69 patients. The study was performed in partnership with researchers at the University of São Paulo’s Ribeirão Preto School of Medicine (FMRP-USP) and resulted in Aline Paixão Becker’s PhD thesis.

BRAF alterations were observed in more than 60% of cases. “Owing to chromosomal alterations, part of the BRAF gene breaks off and fuses with another gene, KIAA1549. This appears to be a very important event in the development of pilocytic astrocytoma,” Reis said.

When the researchers compared the results with data from the patients’ medical histories, they concluded that those with this KIAA1549:BRAF fusion generally fared better than those without.

The FGFR1 mutation was observed in only 7% of the cases investigated, but they were precisely those with the worst clinical outcomes, including the highest risk of recurrence and progression of the disease.

Only one patient had both gene alterations simultaneously. This patient’s clinical outcome was intermediate, i.e., not as good as for the patients with KIAA1549:BRAF fusion only and not as adverse as for those who had only the FGFR1 mutation.

“Because both genetic events affected prognostic evaluation, we combined them in the same analysis and their statistical significance was increased. Patients with KIAA1549:BRAF fusion but no FGFR1 mutation progressed much better than those with the FGFR1 mutation but no fusion. We therefore concluded that these gene alterations can be important biomarkers to help clinicians predict outcomes,” Reis said.

Another potential positive impact of the discovery, according to Reis, is that it could pave the way for studies to test the effectiveness of targeted therapy against the FGFR1 gene.

“Drugs capable of inhibiting the action of FGFR1 are already at the clinical trial stage,” he said. “It’s quite possible that patients with pilocytic astrocytoma who have this gene mutation would benefit from targeted therapy.”

Novel methodology

In partnership with Marileila Varella Garcia, a Brazilian researcher at the University of Colorado Denver in the United States, the Barretos group developed a new probe to investigate the presence of KIAA1549:BRAF fusion in tumor samples.

The probe consists of a DNA fragment containing fluorescent particles that react with BRAF and KIAA1549 so that each gene emits a different color that can be observed using a special microscope.

“In a normal cell, the two genes are in different regions of the genome and the two colors therefore appear separately, but the colors overlap when the genes are fused,” Reis said.

The advantage of the new method, he added, is that it enables scientists to analyze tumor samples conserved in paraffin blocks of the type commonly found in hospitals worldwide.

“The methods typically used until now only allowed us to study frozen tumors. Most institutions lack conditions to maintain a frozen tumor bank.”

The FGFR1 mutation was investigated using conventional gene sequencing methods.

Both gene alterations are considered somatic, meaning they occur during a person’s lifetime and are non-hereditary. Also in both cases, albeit by different mechanisms, the protein encoded by these genes is constantly activated owing to the alteration, favoring cell proliferation.

“Because this is a rare tumor,” Reis said, “we believe the almost 70 cases we sequenced represent a very interesting series and have sufficient statistical power for a biological impact assessment.”

 

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