Genes responsible for glioblastoma multiforme brain cancer

Scientists have identified 18 new genes responsible for driving glioblastoma multiforme, the most common and most aggressive form of brain cancer in adults.

“Cancers rely on driver genes to remain cancers, and driver genes are the best targets for therapy,” said Antonio Iavarone, professor of pathology and neurology at Columbia University Medica.

“We think our study has identified the vast majority of drivers in glioblastoma, and therefore a list of the most important targets for glioblastoma drug development and the basis for personalised treatment of brain cancer,” he said.

Personalised treatment could be a reality soon for about 15 per cent of glioblastoma patients, said Anna Lasorella, associate professor of pediatrics and of pathology & cell biology at CUMC.

The Columbia team used a combination of high throughput DNA sequencing and a new method of statistical analysis to generate a short list of driver candidates.

The massive study of nearly 140 brain tumours sequenced the DNA and RNA of every gene in the tumours to identify all the mutations in each tumour.

A statistical algorithm designed by co-author Raul Rabadan, assistant professor of biomedical informatics and systems biology, was then used to identify the mutations most likely to be driver mutations.

The algorithm differs from other techniques to distinguish drivers from other mutations in that it considers not only how often the gene is mutated in different tumours, but also the manner in which it is mutated.

The analysis identified 15 driver genes that had been previously identified in other studies – confirming the accuracy of the technique – and 18 new driver genes that had never been implicated in glioblastoma.

Significantly, some of the most important candidates among the 18 new genes, such as LZTR1 and delta catenin, were confirmed to be driver genes in laboratory studies involving cancer stem cells taken from human tumours and examined in culture, as well as after they had been implanted into mice.

The study found that half of about 15 per cent of patients have tumours driven by a fusion between the gene EGFR and one of several other genes.

The fusion makes EGFR – a growth factor already implicated in cancer – hyperactive; hyperactive EGFR drives tumour growth in these glioblastomas.

“When this gene fusion is present, tumours become addicted to it – they can’t live without it,” Iavarone said.

We think patients with this fusion might benefit from EGFR inhibitors that are already on the market.

In our study, when we gave the inhibitors to mice with these human glioblastomas, tumour growth was strongly inhibited,” Iavarone said.

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