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Germline BRCA2 Mutations Suspected in Some Primary Brain Cancer Cases

SEATTLE (GenomeWeb) – Though best known for their role in breast and ovarian cancer risk, germline mutations in the BRCA2 gene may also have ties to a subset of primary brain cancer cases, according to research presented today at the National Society of Genetic Counselors' annual education conference.

Michelle Jackson, a genetic counselor and product manager in the field of hereditary breast and ovarian cancer at Ambry Genetics, presented findings from a retrospective analysis that focused in on hundreds of individuals with primary brain cancer patients who'd been tested by hereditary cancer sequencing. Within that group, a significant proportion of individuals had germline mutations in at least one of the 18 genes considered, with 11 individuals carrying suspicious mutations in BRCA2.

Though more follow up is needed, the work hints that "BRCA2 mutation carriers may present with [primary brain tumors], which could have important implications for the provision of genetic counseling and test selection," Jackson and co-author Amanda Bergner, a senior product manager in neurology at Ambry, wrote in a summary of the study prepared for the NSGC meeting.

The analysis is not the first to hint at a role for BRCA2 alterations in brain tumors. In a 2010 article in the Journal of Clinical Oncology, a team from the UK described a 19-year-old man from a breast cancer-prone family who suffered from astrocytoma and was subsequently found to carry a frameshift mutation in BRCA2. Still more examples involving adults or children with gliomas, medulloblastomas, or other brain tumor types have also been described.

Despite such case reports, there has been little in the way of larger-scale studies of BRCA2 as a potential risk factor for primary brain cancer, Jackson noted. That is partly due to difficulties differentiating primary brain tumors from tumors in the brain that have metastasized from other sites — particularly when relying on information provided by individuals describing their family histories.

Similarly, brain tumors diagnosed in individuals who have germline BRCA2 mutations may get lumped into a broader cancer risk syndrome, as shown in a 2003 paper in the Journal of the National Cancer Institute that described several families with Fanconi anemia who carried germline BRCA2 mutations and were inordinately affected by breast and brain tumors.

For their new analysis, Jackson and her colleagues retrospectively reviewed sequential cases involving one or more primary brain tumors that had been tested by hereditary cancer panel testing at Ambry from March 2012 to December 2015.

Of the 364 primary brain cancer patients identified in the analysis, 52 individuals — more than 14 percent — had germline mutations in one of the 18 genes considered on the hereditary cancer risk panel, which covered genes such as BRCA2, CHEK2, TP53, PMS2, APC, and so on. Eleven of those cases were marked by BRCA2 mutations, including eight individuals whose first primary brain tumor occurred in the brain.

Brain tumors can arise from neuronal or brain support cell types, producing tumors on a spectrum from benign and relatively harmless to malignant and aggressive, Jackson noted. In the group of 11 BRCA2 mutation carriers, she and Bergner identified individuals with a spectrum of tumor types — from astrocytomas and glial tumors such as glioblastoma or glioma to meningiomas (a type of brain tumor that is often benign).

In their small group of BRCA2 mutation carriers, the researchers found that all three cases involved meningioma tumors in individuals who had initially been diagnosed with breast or ovarian cancer.

And while the average age at diagnoses was almost 42 years old across the group with primary brain cancer as a whole, those with germline mutations in BRCA2 tended to be diagnosed with the disease when they were slightly younger — around 34 years old, on average.

"Given the increasing opportunity to effectively treat certain types of brain tumors based on underlying genetic mutations, and the potential impact of heritability within the family, exploring the contribution of germline mutations to the development of [primary brain tumors] is important for appropriate medical management and genetic counseling," Jackson and Bergner noted.