Four New Breast Cancer Susceptibility Genes Discovered—One with a Twist

Genetics and cancer have a turbulent relationship. If genetic material becomes damaged, it can change how a cell functions. Changes (or mutations) can lead to cancer if they occur in genes that control cell growth, death, and repair. When a mutated gene increases the risk of cancer, it is called a cancer susceptibility gene.

The hunt for new cancer susceptibility genes is a tireless one. For researchers at Huntsman Cancer Institute (HCI) at the University of Utah (U of U), the history of this pursuit is illuminated with groundbreaking discoveries such as uncovering BRCA1, BRCA2, APC, CDKN2A/p16, and XRCC2 (see figure below).

HCI investigators Sean Tavtigian, PhD, and David Goldgar, PhD, lead an international consortium working to find more gene mutations that cause inherited breast cancer susceptibilities. In 2014, two of their studies added four genes to the list.

Tavtigian and Goldgar collaborated with Melissa C. Southey, PhD, professor in the Department of Pathology at the University of Melbourne, Australia, on both studies.

For the first study, the researchers used a technique called whole exome sequencing. This technology looks for genetic changes in all genes in the human genome. “We start by looking at all the genes at once,” explains Goldgar, professor in the Department of Dermatology at the U of U. “Then we pinpoint the genes with interesting changes that show the gene not working properly in familial breast cancer cases.”Tavtigian and Goldgar

When the investigators used this technology to examine families with a history of breast cancer, mutations in a gene called RINT1, involved in important cellular processes including DNA repair, stood out. Further investigation revealed that families with RINT1 mutations not only had a two- to three-fold increased risk for breast cancer, but a similarly increased risk for gastrointestinal and gynecological cancer as well.

RINT1 was not initially a very strong candidate for a breast cancer susceptibility gene,” says Tavtigian, associate professor in the Department of Oncological Sciences at the U of U. “Our finding that it was not only a breast susceptibility gene, but also a susceptibility gene for several other cancers, was quite surprising.” The results were published in the May 2014 edition of Cancer Discovery.

The second study—led by Tavtigian and published in the June 2014 edition of Breast Cancer Research—confirmed that mutations in three other genes increase breast cancer risk. Genes MRE11A, RAD50, and NBN encode proteins involved in DNA repair and were previously on cancer scientists’ radar as possible susceptibility genes.

The relationship between these two discoveries is still unclear. “Interestingly, RINT1’s name is an abbreviation for ‘RAD50 Interactor 1,’” says Tavtigian. “We know there’s a connection between RINT1 and MRE11A, RAD50, and NBN, but we don’t know if it explains why RINT1 is a susceptibility gene.”

Today, almost 50% of the familial risk for breast cancer can be explained by mutations in susceptibility genes, compared to about 30% only five years ago. Families with a known increased risk have a powerful defense against the disease. Early and increased screening, in addition to preventive measures such as exercise and other healthy lifestyle factors, provide a head start in catching and reducing the risk of cancer. Every new mutation discovered empowers more families.

For more information about familial breast risk, visit the High Risk Breast Cancer Clinic and the Family Cancer Assessment Clinic webpages.

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More than Alphabet Soup: What’s in a Gene Name?alphabet soup

BRCA1 and BRCA2: Named for their relationship to breast cancer (BReast CAncer), specific inherited mutations in these genes significantly increase the risk of several cancers, including breast and ovarian. Learn more about BRCA1/2.

APC: Adenomatous polyposis coli (APC) causes a condition called familial adenomatous polyposis (FAP). Most people with FAP develop colon cancer. Learn more about APC and FAP.

CDKN2A/p16: Of families with an increased risk of developing melanoma, 35% to 40% have mutations in cyclin-dependent kinase inhibitor 2A, or CDKN2A. Learn more about CDKN2A/p16.

XRCC2: With the official full name, X-ray repair complementing defective repair in Chinese hamster cells 2 (whew!), XRCC2 was added to the list of breast cancer susceptibility genes in 2012. Read about the discovery of the XRCC2 by Tavtigian and Goldgar in our 2012 Top Science Report.