Tumours reveal novel genetic disruption in DNA

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Source: Gulf News

Scientists who scoured the DNA of brain tumours, searching gene by gene for bad actors, were puzzled. The cancers had none of the mutations in growth-causing genes that are typical of other tumours, yet they grew quickly, with no brakes. The question was why — what had altered their genetic instructions to lead to runaway cell division?

The surprising answer, researchers reported in November 2015 in the journal “Nature”, is that the three-dimensional structure and organisation of the DNA had been disrupted. As a result, two genetic neighbourhoods that are usually separated, as if they are two gated communities, were merged. The effect was to allow a powerful snippet of DNA from one neighbourhood into the one next door, where it woke up a near-dormant growth gene. And the cells took off.

This is an entirely new way for cells to become cancerous, researchers said, and is probably not unique to the brain cancers, low- and intermediate-grade gliomas, that were the subject of the new study. Its lead author, Dr Bradley E. Bernstein, a member of the Broad Institute in Cambridge, Massachusetts, and a pathology professor at Massachusetts General Hospital, says he has already found a similar phenomenon in about a dozen other tumours. And, he says, the discovery suggests a potential treatment with an existing chemotherapy drug that restores the walls separating the DNA sections.

“It’s really exciting,” said Dr Peter Dirks, a brain cancer expert at the Hospital for Sick Children in Toronto, adding that at least with gliomas, the suggested treatments could be tested in clinical trials very soon.

The finding was surprising, others said.

“What this tells me is that I know a lot less than I did before,” said Dr Jeremy Rich, a brain cancer expert at the Cleveland Clinic.

Gliomas are the most common type of malignant brain tumour in adults — about 18,000 are diagnosed each year in the United States. The most aggressive gliomas, known as glioblastomas — the type of cancer that killed Senator Edward M. Kennedy — usually strike older people and have an average survival time of 18 months. The lower-grade ones tend to strike younger adults, and survival times can be much longer. Yet despite extensive study of gliomas, doctors have made little progress in treating them. Doctors usually remove the lower-grade tumours and treat patients with radiation and chemotherapy. But the tumours return, often as aggressive glioblastomas that resist cancer therapies.

“We are desperate in this disease,” Dirks said.

The researchers did, however, notice one puzzling feature in up to 80 per cent of low- and moderate-grade gliomas — a common gene that seemed to have no particular relevance to cancer was often mutated. The gene, isocitrate dehydrogenase, or IDH, had long been considered humdrum, a so-called housekeeping gene that directs cells to make an enzyme used in energy production.

“It was really surprising,” Bernstein said. “Why would a metabolism gene cause cancer?”

But then again, why was it mutated so often?

“That frequency is just shockingly high,” said Dr Ingo K. Mellinghoff, a brain cancer expert at Memorial Sloan Kettering Cancer Center. “It makes you think it must be important.” And, he said, the mutation is one of the very first changes in the cancer cells.

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