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Scientists Discover Gene Linked to Breast and Ovarian Cancer

Finding could have implications for genetic testing and targeted prevention (Dec. 17)

Researchers led by the Institute of Cancer Research, London, have found that rare mutations in a gene called PPM1D are linked to an increased risk of breast and ovarian cancer. The mutations are not inherited, and the discovery potentially reveals a new mechanism of cancer development.

The new findings were published online in Nature.

The study suggests that about 20% of women with PPM1D mutations will develop breast or ovarian cancer in the course of their lifetime — almost double the breast cancer risk and more than ten times the ovarian cancer risk of women in the general population. The new discovery could have implications for genetic testing and targeted prevention, particularly for ovarian cancer, which is often diagnosed at an advanced stage.

The investigators analyzed 507 genes involved in DNA repair in 1,150 women with breast or ovarian cancer and identified PPM1D gene mutations in five women. They then sequenced the PPM1D gene in 7,781 women with breast or ovarian cancer and in 5,861 people from the general population. The researchers identified 25 faults in the PPM1D gene in women with cancer and only one in the general population –– a highly significant difference.

The study found that the mutated genes were not passed down from parent to child and were not present in every cell. Moreover, there were no PPM1D mutations in the cancer cells or in the normal breast or ovarian cells; they were found only in blood cells. These findings suggest that PPM1D works in a different way to other genes known to increase the risk of breast and ovarian cancer, such as BRCA1 and BRCA2, possibly revealing a new cancer-causing mechanism.

The team found that the mutations made the molecule that is produced from the PPM1D gene shorter than usual. Such truncating mutations are usually thought to cause a loss of function; however, the investigators were surprised to find that in this case the PPM1D mutations seem to make the molecule more active.

“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,” said study leader Professor Nazneen Rahman.

“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.”

Source: Wellcome Trust; December 17, 2012.

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