Missing gene may drive more than one in four breast cancers

More than one out of every four cases of breast cancer is associated with a specific, missing gene, a finding that could have significant implications for chemotherapy treatments, according a recent study by Cornell University researchers.

The study shows that the lack of a certain gene occurs in almost 28 per cent of human breast cancers, playing a role in some 60,000 breast-cancer cases in the United States and 383,000 worldwide this year. Posted online in the journal Genetics, the study has important clinical implications; it suggests that several existing drugs may be effective in treating breast cancers with the missing gene, called NF1.  It also suggests that the commonly used breast cancer drug tamoxifen could make the disease worse in these specific cancers.

The NF1 gene negatively regulates one of the most important oncogenes – genes that when mutated or expressed at high levels contribute to turning a normal cell into a cancerous one. This oncogene, called RAS, is involved in signalling inside the cell to control growth. When NF1 is missing or depleted, RAS becomes hyperactivated and can lead to tumour formation.

In the study, Cornell researchers used a mouse model with elevated mutation rates that led to breast cancer in 80 per cent of the mice.

''These mice almost always get mammary tumours, and when we looked at their genomes, nearly all of them were missing this NF1 gene,'' said John Schimenti, professor of genetics at Cornell's College of Veterinary Medicine and the paper's senior author. ''There are many big cancer studies that identify the most commonly mutated genes, but they don't prove experimentally that those genes are the drivers of cancer.''

In humans, there are many causes of breast cancer, and each patient's cancer has a slightly different set of natural gene variants as well as new mutations in their tumors, so identifying individual genes that drive cancer can be problematic. But the model mice are inbred and get exactly the same tumour every time. ''So we've eliminated all the noise,'' allowing the researchers to identify NF1 as a driver of these tumours, said Schimenti.