Molecular biology study by Abu Dhabi researcher has cancer breakthrough potential

Few areas of science are advancing as rapidly as molecular biology.

It is 64 years since James Watson and the late Francis Crick published their famous double-helix model for the structure of DNA, the genetic material, and since then progress has happened at an ever-faster pace.

The practical results of this have been seen in everything from genetically engineered crops to more effective treatments for disease.

A study by Dr Youssef Idaghdour, an assistant professor of biology at New York University Abu Dhabi, could offer further advances by suggesting pointers that could help develop cancer drugs. It could also help clinicians to understand why some patients respond better than others to treatment.

The focus is on a molecule closely related to DNA called ribonucleic acid (RNA) and, in particular, a form called transfer RNA (tRNA).

Published in the journal Genome Medicine and written with Dr Alan Hodgkinson, from the Department of Medical and Molecular Genetics at King’s College London, the work is focused on tRNA within mitochondria, which are “organelles” involved in energy production within cells. Mitochondria have their own genetic material separate to that of cell nuclei.

The researchers looked at the extent to which tRNA has methyl groups, which consist of one carbon atom and three hydrogen atoms, attached to it.

The methylation of DNA or RNA has become a major area of focus for molecular biologists. It is part of the field of epigenetics, which looks at how characteristics develop and can be transmitted based upon how genes are expressed, instead of simply what the sequence of DNA is.

Interest in epigenetics in relation to cancer is “huge”, said Professor Stephan Beck, a German-trained researcher who is professor of medical genomics at University College London.

“It’s well established and the expectation is that this field will become much, much bigger than it currently is,” he said.

“Cancer is the consequence of genetic and epigenetic changes - that’s what cancer is. That’s why so much research goes on.”

Transfer RNA is involved in the events required for a gene to produce a protein. The double-stranded DNA opens up and is initially transcribed into a strand of messenger RNA (mRNA).

Translation comes next, involving a tRNA molecule with an amino acid attached to it bonding temporarily to a strand of mRNA with a complementary chemical sequence. This allows the amino acid to link itself to the growing protein molecule for which the gene codes.

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In the recently published research, a genetic analysis was carried out on mitochondrial tRNA data generated from 1,226 samples of normal human tissue or tumour tissue by The Cancer Genome Atlas (TGCA) project. These samples, taken from a database, were paired, so that for any given sample of normal tissue there was a cancerous sample from the same individual.

Dr Idaghdour and Dr Hodgkinson found that tumour samples tended to have higher methylation levels than normal samples, a pattern seen across multiple cancer types.

“For a patient, if the methylation of their mitochondrial tRNA [in normal tissue] tends to be low, the moment they have cancer, they tend to have significantly higher levels. The question is, ‘What is it doing?’” said Dr Idaghdour, a Moroccan scientist who studied for his PhD in the United States before undertaking post-doctoral research in Canada.

Dr Idaghdour and Dr Hodgkinson think methylation patterns may affect translation and in doing so cause mitochondria to produce more energy. This, in turn, allows cells to divide faster and helps the tumour to grow.

“You can think about developing drugs that would block the cancer cell from making this modification [to the methylation levels]; that’s how you would make the link to potential therapeutics. The methylation would stay the same as a normal cell,” said Dr Idaghdour.

In a further key finding, a genetic analysis by the researchers found that 18 positions on the nuclear DNA of individuals influenced the degree to which their mitochondrial tRNA became methylated. This means that individuals with particular genotypes were liable to see the methylation of their mitochondrial tRNA increase very rapidly when they developed cancer, while individuals with other genotypes saw much less of a change. In some cases those patients with less of a change in methylation were more likely to survive cancer. This suggests a way in which measuring the extent of methylation could be useful to clinicians.

“You could use the rate of methylation as a biomarker. [If the] individual has high methylation, the clinician can be more aggressive in terms of treatment,” said Dr Idaghdour.

Any potential use in a clinical setting of Dr Idaghdour’s research would be many years away and it is not clear yet whether it could be turned into improved methods to treat particular forms of cancer.

But the potential for this to happen is there, since there have been other cases where methylation has been used in the development of cancer treatments.

Professor Robert Brown, head of the cancer division at Imperial College London, said that, until now, most research has been on DNA methylation, rather than RNA methylation, which this latest study looks at.

Demethylating agents, which can prevent aberrant patterns of gene expression associated with cancer, are being used to combat some forms of cancer.

“Looking at DNA methylation and other epigenetic changes has tended to lag behind the classical genomic analysis but there’s a lot of really good technologies coming through that allow one to look at DNA methylation,” he said.

He described RNA methylation as “a very emerging area”.

“There’s good evidence emerging about the biological significance of [RNA methylation]. The clinical relevance of it in terms of cancer is still to be evaluated,” he said.

Although the ultimate significance of Dr Idaghdour and Dr Hodgkinson’s findings is yet to be determined, they are operating at the cutting edge of a field that could in years to come offer important benefits to patients.