Aggressive brain cancer linked to gene fusion

Some cases of glioblastoma - a particularly aggressive form of brain cancer - may be due a genetic mutation where two separate genes fuse into one, scientists report.

In research published in the journal Science, blocking the activity of the protein produced by this mutation slowed down the progression of the disease in mice.

The study, led by Professor Antonio Iavarone at Columbia University in New York, USA, began with detailed genetic analysis of cells from nine glioblastoma patients. After identifying mutations that the researchers suspected might be involved in the disease, they extended their analysis to another 97 samples from glioblastoma patients registered with the Cancer Genome Atlas project (see story in BioNews 666).

In 3% (percent) of the glioblastoma cases studied, the gene fusion mutation was implicated. Under normal conditions, the two genes produce separate proteins that ensure even distribution of chromosomes in the two daughter cells resulting from cell division, or mitosis.

The gene product of the fused genes takes on this function but performs it in unusual places or contexts; the proteins 'do their thing, but incorrectly', co-lead author Dr Anna Lasorella told New Scientist. As a result, the mutation causes uneven distribution of the chromosomes in the daughter cells. This is called aneuploidy, and is a hallmark of cancer cells.

Professor Iavarone called his team's findings 'doubly important. From a clinical perspective, we have identified a druggable target for a brain cancer with a particularly dismal outcome. From a basic research perspective, we have found the first example of a tumour-initiating mutation that directly affects how cells divide, causing chromosomal instability'.

In their study, the scientists also introduced the mutation into healthy mice and over 90% developed an aggressive brain tumour. Administration of drugs inhibiting the protein's activity slowed progression of the disease and came close to doubling the life-span of the mice with cancer.

Professor Stephen Emerson, director of the Herbert Irving Comprehensive Cancer Centre at Columbia University Medical Centre said the study was 'perhaps a first step toward a personalised, precision approach to the treatment of glioblastoma'.

Speaking to the Press Association for Cancer Research UK, Peter Collins, professor of neuroscience at the University of Cambridge, who was not involved in the study, commented: 'With more and more of these "next-generation" gene sequencing projects reporting over the coming years, more drug targets will be identified'.