Media Centre – IARC News

New breast cancer susceptibility gene found

Rare Mutations in XRCC2 Increase the Risk of Breast Cancer
D.J. Park, F. Lesueur, T. Nguyen-Dumont, M. Pertesi, F. Odefrey, F. Hammet, S.L. Neuhausen, E.M. John, I.L. Andrulis, M.B. Terry, M. Daly, S. Buys, F. Le Calvez-Kelm, A. Lonie, B.J. Pope, H. Tsimiklis, C. Voegele, F.M. Hilbers, N. Hoogerbrugge, A. Barroso, A. Osorio, the Breast Cancer Family Registry, the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, G.G. Giles, P. Devilee, J. Benitez, J.L. Hopper, S.V. Tavtigian, D.E. Goldgar, M.C. Southey.
The American Journal of Human Genetics, Volume 90, Issue 4, 734-739, 29 March 2012. doi:10.1016/j.ajhg.2012.02.027

Read article at the AJHG website

Currently, only about 30% of the familial risk of breast cancer has been explained, leaving the substantial majority still unaccounted for. In a large collaborative study led by Professor Melissa Southey at the University of Melbourne and Associate Professor Sean Tavtigian and Professor David Goldgar at the University of Utah, we found that mutations in a gene called XRCC2, although rare, explain another proportion of breast cancers that run in families where there is no known genetic cause and that particularly occur at an early age.

It is a significant discovery and XRCC2 is the first breast cancer susceptibility gene to be discovered using the massive parallel sequencing technology, which allows analyzing the DNA sequence of all the genes in the genome in a single experiment (exome sequencing).

In an exploratory phase, collaborators from the International Agency for research on Cancer (IARC) performed exome sequencing in affected patients from families that have a strong history of the disease but do not carry mutations in the currently known breast cancer susceptibility genes. From the exome sequencing data, two different types of XRCC2 mutations were identified in two families originating from Australia and the Netherlands. One type of mutation causes the gene to create an incomplete and dysfunctional version of the protein; the other type occurs when a single amino acid in the protein is changed, that is likely to affect the protein function. Like most of the known breast cancer genes, XRCC2 is involved in a particular type of DNA repair. This prompted us to further investigated the XRCC2 gene in a larger series of studies using DNA from blood samples of 689 families with multiple members affected with breast cancer in Melbourne, and from 1,308 women who were affected at an early age by breast cancer and recruited from the general population, as well as 1,120 controls at the IARC. More XRCC2 mutations were detected in breast cancer cases but not in the controls, implicating this gene in breast cancer susceptibility.

A worldwide effort has already been launched to figure out what fraction of breast cancer is attributable to mutations in this gene and how high the risk conferred by these mutations actually is.

In terms of clinical applications, this discovery could help manage the risk of breast cancer in families with a strong history of the disease and no known genetic cause. It will assist some families to determine individual risk and identify family members who are at high risk of developing the disease. Unaffected individuals carrying a mutation in this gene could also be offered predictive testing, subsequent genetic counseling and ongoing clinical management on the basis of their mutation status. People whose breast cancer is associated with XRCC2 mutations could also benefit from specific treatments that target the genetic fault such as PARP inhibitors.

Applying this study approach and analytical strategy of the DNA sequence variants, we believe that further breast cancer susceptibility genes, or genes predisposing to other common cancers, will be identified at a faster rate than before.

The research was conducted in a large collaborative network including researchers from research organizations based in North America, Australia, and Europe. The study was supported by funding from the National Institutes of Health (R01CA155767 and R01CA121245) plus several other worldwide research foundations. The study also benefited from resources gathered by the Breast Cancer Family Registry, the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, and several other breast cancer research efforts taking place around the world.