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Genetic Discovery May Explain Cancer Risk Mystery

Some common genetic cancer mutations could indicate the presence of more influential rare mutations that have yet to be found.

The finding, published in PLOS Genetics, could help explain why research into the genetic causes of common diseases has failed to explain more than a fraction of the heritable risk of developing them, and could lead to earlier detection of prostate cancer.

“Some have long suggested that DNA variations across the genome, which were found to have a weak association with diseases, are actually an artefact of another, hidden variant,” said Professor Graham Giles of the University of Melbourne.

“By collaborating on this very large study we were able to do ‘fine mapping’ work to measure a huge number of variants in the DNA for the gene HOXB13, and we did in fact discover that a rare variant was more strongly associated with risk of prostate cancer. We believe this to be the first such example.”

Prostate cancer is the most common cancer diagnosed in Victorian men, with almost 4800 new cases recorded by the Victorian Cancer Registry in 2012 – accounting for 30% of all cancers.

While the majority of men will develop some form of prostate neoplasm during their lifetime, these usually progress slowly and remain asymptomatic until their death, with only a proportion of prostate tumours requiring clinical intervention.

Giles said that while the study did not indicate how widespread the phenomenon of rare variants may be, it does demonstrate the importance of digging deeper to identify the causal genetic changes behind common variants that have already been shown to influence risk of disease.

“If there is a small group of people who carry a rare genetic mutation, which is strongly associated with risk of certain cancers, then we may be able to use targeted screening to identify those at risk earlier,” he said.