Massive study identifies potential new targets for brain cancer treatments

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London, September 5 : American researchers have identified some new genetic changes that may be targets for future therapies to treat brain cancer.

The breakthrough results from the efforts made by scientists from Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard, as well as their collaborating investigators from 18 institutions and organizations.

The researchers say that the large-scale combing of the brain cancer genome, part of the 100million dollar pilot project of The Cancer Genome Atlas (TCGA), has also enabled them to confirm the key roles that some of the previously known mutated genes play in glioblastoma multiforme (GBM), the most aggressive type of primary brain tumour.

"The findings of significant mutations in genes that have implications for therapeutic development illustrate precisely how unbiased and systematic cancer genome analyses can lead to paradigm-shifting discoveries," Nature magazine quoted Dr. Lynda Chin, who chairs the GBM disease working group within TCGA, as saying.

"These data show that this approach, of looking at large numbers of tumours and a large number of genetic factors, can be done and the results are really valuable. We have made significant novel findings, and the reproducibility of the data is high," added Dr. Matthew Meyerson, who co-led the writing effort for the first summary of data from the pilot project.

The research collaborators analysed the complete sets of DNA of tumour samples donated by 206 patients with GBM.

They looked for several categories of flaws-"typos" in the DNA code of a gene that alters its function; too many or too few copies of a given gene; damage to chromosomes causing loss or dislocation of pieces; gene activity that is higher or lower than normal; and changes in DNA methylation-by turning genes on or off without affecting their structure.

The team also had access to information on how the patients who donated the samples had fared, including how they responded to certain drugs.

While five major gene mutations have previously been identified in glioblastoma cells, the new sequencing effort revealed three that hadn't been discovered.

The researchers say that one mutation affects the NF1 gene that causes neurofibromatosis, a second mutation is in the ERBB2 gene known to be involved in breast cancer, and the third affects a gene in the PIK3 signaling pathway that is abnormally activated in a number of cancers.

They, however, add that a particular gene called PIK3R1 had been only rarely implicated in any cancer.

"Each of these mutated genes defines a new target for glioblastoma treatment," said Meyerson.

The researchers also found that three signalling pathways, networks of genes and proteins that act together to carry out a cellular function, were disrupted in more than three-quarters of the GBM tumours.

They revealed their identity as the cyclin-dependent kinase/retinoblastoma pathway that regulates cell division, the p53 tumour suppressor pathway that is involved in response to DNA damage and cell death, and the receptor tyrosine kinase pathway that carries signals that control cell growth.

Chin said that the most exciting finding was that the multipronged study design also enabled the scientists to make a potentially important connection between a methylation change in the glioblastoma cells and which drugs should be used for treatment.

Brain tumours that contain a silenced form of a gene known as MGMT are known to be more susceptible to cancer drug temozolomide (Temodar), and thus it is routinely given along with radiation to patients with MGMT methylation.

However, the study suggests that when patients treated with Temodar subsequently have a recurrence of the tumour, it is very likely to become resistant to treatment because of "hypermutation", an increased rate of gene changes that led to the tumour's ability to evade the drugs.

"This could have immediate clinical applications," said Chin.

The authors of the study say that these findings are only the tip of an expected iceberg, and that the "most powerful impact" is expected to come from further research studies.

"These impressive results from TCGA provide the most comprehensive view to date of the complicated genomic landscape of this deadly cancer. The more we learn about the molecular basis of glioblastoma multiforme, the more swiftly we can develop better ways of helping patients with this terrible disease. Clearly, we should move ahead and apply the power of large-scale, genomic research to many other types of cancer," said NIH Director Dr. Elias A. Zerhouni.

ANI

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