A team of researchers led from The Institute of Cancer Research, London, have found that mutations in a gene called PPM1D are linked to an increased risk of breast and ovarian cancer – through what may be a new mechanism of cancer development.

Women with PPM1D mutations have a 20 per cent chance of developing breast or ovarian cancer – double the breast cancer risk and over 10 times the ovarian cancer risk of women in the general population.

The discovery could have implications for genetic testing and targeted prevention in particular for ovarian cancer, which is often diagnosed at an advanced stage.

And intriguingly, PPM1D seems to be working in a completely different way to other genes known to increase the risk of breast and ovarian cancer, such as BRCA1 and BRCA2.

We have two copies of every gene. In most cancer-causing genes a mutation in one copy is inherited and present in every cell, with the second copy mutated in the tumour itself.

However, in this case the team found PPM1D mutations were not inherited and rather than being present in every cell, were only found in blood cells.

Even more surprisingly, there were no PPM1D mutations in the cancer cells or in the normal breast or ovarian cells.

The mutations make PPM1D overactive, which in turn reduces the action of a gene called TP53, which is the most frequently mutated gene in cancer cells.

This important discovery is published in the journal Nature this week, and may signify a new cancer-causing mechanism.

Study leader Professor Nazneen Rahman, head of genetics at The Institute of Cancer Research (ICR) and head of the cancer genetics clinical unit at The Royal Marsden NHS Foundation Trust, said: “This is one of our most interesting and exciting discoveries. At every stage the results were different from the accepted theories. We don’t yet know exactly how PPM1D mutations are linked to breast and ovarian cancer, but this finding is stimulating radical new thoughts about the way genes and cancer can be related.

“The results could also be useful in the clinic, particularly for ovarian cancer which is often diagnosed at an advanced stage. If a woman knew she carried a PPM1D mutation and had a one in five chance of developing ovarian cancer, she might consider keyhole surgery to remove her ovaries after completing her family.”

Revolutionary new sequencing technologies that allow much deeper analysis of genes were crucial to the discovery. The PPM1D mutations were only present in some cells – a so-called mosaic pattern, which is difficult to detect with older sequencing methods. It is very possible that similar mosaic mutations in other genes, and in patients with other types of cancer, will emerge as many groups are now doing deep sequencing research.

The team analysed 507 genes involved in DNA repair in 1,150 women with breast or ovarian cancer, identifying PPM1D gene mutations in five women. They then sequenced the PPM1D gene in 7,781 women with breast or ovarian cancer and 5,861 people from the general population. There were 25 faults in the PPM1D gene in women with cancer and only one in the general population, a highly statistically significant difference.

Professor Alan Ashworth, chief executive of The Institute of Cancer Research and one of the study researchers, said: “This discovery really does turn conventional wisdom about the way genetic mutations can lead to cancer on its head. As we unravel this puzzle, we are likely to gain valuable insights about how cancer develops, and new tools for assessing people’s risk of the disease and targeting preventive treatment.”

The study was funded by the ICR, the Wellcome Trust, Cancer Research UK and Breakthrough Breast Cancer.

Dr Michael Dunn, Head of Molecular and Physiological Sciences at the Wellcome Trust said: “This study is a fantastic example of the power of next generation sequencing to discover new cancer predisposing genes, offering opportunities for better diagnosis. The discovery also opens up a very exciting new avenue of research in the study of cancer development."

Source: ICR