Breast cancer gene carriers risk amplified by additional genes

Many women with a faulty breast cancer gene could be at greater risk of the disease due to extra ‘risk amplifying’ genes, according to research to be published in theAmerican Journal of Human Genetics on 20 March 2008.

Cancer Research UK scientists have found that common versions of two genes (FGFR2 and TNRC9) – known to increase breast cancer risk in the general population – also increase the risk in women carrying damaged versions of the BRCA2 gene.

Around one in 18 women will develop breast cancer by the age of 65. On average, half of women carrying a faulty BRCA2 gene will develop the disease by the age of 70.

This study found that particular combinations of the FGFR2 and TNRC9 genes modify breast cancer risk in BRCA2 mutation carriers.

One per cent of BRCA2 mutation carriers have the highest risk combination of FGFR2 and TNRC9 genes. Seven in every 10 women in this category are predicted to develop breast cancer.

Around 20% of the BRCA2 mutation carriers have the lowest risk combination of the FGFR2 and TNRC9 genes. The researchers found that their risk is lowered so 4 in every 10 women in this category are expected to develop the disease.

These findings are the first step in a series of studies hunting for breast cancer susceptibility genes, which aim to better monitor and treat women with a family history of the disease.

“This is the first time we have found evidence that common changes in other genes can amplify the risk of breast cancer in women known to have faulty BRCA genes,” said Lead author Professor Doug Easton, director of Cancer Research UK’s Genetic Epidemiology Unit at the University of Cambridge.

“This is the first step in finding a set of genes that modify the risk in BRCA carriers, and may influence how we monitor women with a family history of the disease.”

The study brings together results from international research groups looking at a total of more than 10,000 women carrying a BRCA1 or BRCA2 mutation.

Professor Georgia Chenevix-Trench and colleagues at the Queensland Institute of Medical Research, who are co-authors on the AJHG paper, contributed data from the Kathleen Cuningham Consortium for Research into Familial Breast Cancer (kConFab) and controls from the Australian Ovarian Cancer Study. kConFab cases are particularly informative for these studies because of their strong family history of breast cancer.
“It’s important to remember that the prevalence of this combination of gene faults is rare in the general population,” said Professor Chenevix-Trench. “But advances like this will add to our ability to identify those most at risk for clinical monitoring, detecting the disease earlier in those who develop it.”
NOTES TO EDITORS

1. Common breast cancer predisposition alleles modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Antonis C Antoniou et al. 2008. American Journal of Human Genetics.
2. The gene, MAP3K1 was associated with a change in breast cancer risk in BRCA2 carriers.
3. TNRC9 was also associated with a change in breast cancer risk in BRCA1 carriers.
4. Around 1 in 800 women in the UK carry a faulty BRCA1 gene and 1 in 500 carry a faulty BRCA2 gene.
5. Around 1 in 20 cancers are thought to be caused by high-risk faulty genes inherited from one or both parents.
6. Women carrying the BRCA1 and BRCA2 mutation have a 50–80% chance of developing breast cancer and an increased risk of developing ovarian cancer.