Rare Genetic Mutations Tied to Higher Risk of Breast Cancer

Rare Genetic Mutations Tied to Higher Risk of Breast Cancer

Certain rare genetic mutations, similar to the more common BRCA1 and BRCA2 mutations, are also associated with an increased risk of breast cancer, according to a large global study led by researchers at the University of Melbourne and Cancer Council Victoria.

The study, “PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS,” published in the Journal of Medical Genetics, may improve counseling and clinical guidelines for carriers of these mutations, with the possible recommendation of preventive treatments, such as prophylactic mastectomy.

The genes whose mutations were identified in this study, PALB2, ATM, and CHECK, were already considered breast cancer susceptibility genes, and included in the genetic screening tests. But because these mutations are extremely rare, there were no accurate estimates of the breast cancer risk associated with such mutations.

“Our previous studies highlighted these as genes of interest, and this has led to women being screened for changes to these genes, but we haven’t had enough information to inform advice,” Professor Melissa Southey, of the University’s Centre for Cancer Research at the Victorian Comprehensive Cancer Centre (VCCC), said in a press release. “It’s only by screening the DNA of tens of thousands of people in different countries that we have gained a clearer picture of their significance in causing cancers.”

Southey and Associate Professor Roger Milne led an international effort to assess the genetic mutations of nearly 200,000 patients with prostate, ovarian, or breast cancer, who had taken part in 120 studies in Europe, Australia, Asia, and Africa.

The team was able to confirm that mutations in all three genes were associated with significantly increased risk for breast cancer. In particular, participants with PALB2 mutations had a risk 3.44- to 4.21-fold higher, and those with a particular mutation in ATM were 11 times more likely to develop the disease. Also, three mutations in CHEK2 were found to increase the risk for breast cancer, ranging from 1.33- to 5.06-fold increase compared to those without the mutations.

“PALB2 and ATM can now be confidently included in testing,” Southey said.

This is the first study of this scale focusing on rare mutations. Although each rare mutation only affects one or two patients in a particular study, this translates into several thousands of patients worldwide.

Patients with specific mutations in the CHEK2 gene also had an increased risk for prostate cancer, suggesting that screening for these rare mutations may influence not only the management of breast cancer patients, but also of men with prostate cancer.

“The same mutation might cause breast cancer in one person and a different cancer in another, or might cause multiple cancers in the same person, and all these cancers might respond to the same drug,” said Roger Milne, deputy director of Cancer Epidemiology at the Cancer Council Victoria and associate professor at the University’s Centre for Epidemiology and Biostatistics. “Ultimately, the more we know about the different mutations, the closer we will get to personalising treatments.”

Southey and Milne are now exploring the impact of an additional 2,000 rare genetic mutations, and expect to release data in 2017.

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