The efforts of researchers from around the world led to the discovery of mutations in a gene called XRCC2 as a cause of increased breast cancer risk. “We have added to the list of genes that harbor mutations causing this disease,” says Sean Tavtigian, PhD, a Huntsman Cancer Institute (HCI) investigator and associate professor in the Department of Oncological Sciences. “This knowledge will improve breast cancer diagnostics and add years to patients’ lives.” The discovery was published in the April 2012 issue of The American Journal of Human Genetics and named one of its top five papers of 2012.

Tavtigian and David Goldgar, PhD, an HCI investigator and professor in the Department of Dermatology, teamed up with Melissa Southey, PhD, a professor in the Department of Pathology at the University of Melbourne in Australia, to head the study.

Discovered more than a decade ago at the University of Utah, BRCA1 and BRCA2 are the most well-known gene mutations that increase breast cancer risk, yet their effects explain less than one-third of breast cancers associated with family history. This collaborative study looked for families around the world with a history of the disease and no mutations in known susceptibility genes.

“The criteria for inclusion in the study were quite strict,” says Goldgar. “Basically it comes down to families with a strong history of breast cancer (families with more than four cases of early onset disease) who have been tested for and don’t have mutations in BRCA1 or BRCA2.”

The researchers used a technology called exome capture massively parallel sequencing (exome sequencing), which shows the exact order of the nucleotides (the four building blocks of DNA) in all of the protein coding genes in the human genome. The ability of this technology to analyze the DNA of all of the genes in a single experiment, according to Tavtigian, makes it an amazingly powerful tool for genetic research. From the exome sequencing data, they found two XRCC2 mutations occurring in breast cancer patients.

This discovery has promising implications for these patients and their families. Research suggests that XRCC2 may provide a target for chemotherapy. A type of drug called a PARP inhibitor appears to kill tumor cells that have gene mutations in a particular DNA repair pathway. XRCC2 is in this pathway, as are BRCA1 and BRCA2. The researchers believe it’s likely that a breast cancer patient who has a mutation in XRCC2 will respond well to treatment with this drug.

As for cancer prevention,“Relatives who have not yet been affected by the disease but carry the mutations will benefit,” says Tavtigian. “They can find out they are at risk before they have cancer and take action to reduce their risk or catch the cancer early.” Further research is underway to determine what fraction of breast cancer is caused by these mutations and how much they increase a person’s breast cancer risk.

If you have a family history of breast cancer and want to learn more about your risk, contact HCI’s Family Cancer Assessment Clinic (FCAC) and ask about genetic counseling.