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Sandy Srinivas, MD


Novel BRCA2 Mutation Strengthens Evidence for Germline Genetic Testing

By: Celeste L. Dixon
Posted: Tuesday, February 14, 2023

An extremely rare BRCA2 L105X mutation identified in a large extended family in Tasmania, Australia, seems to be strongly associated with a predisposition to prostate cancer as well as breast cancer. The mutation had been reported in the literature in just one previous family with five cases of breast cancer and one case of ovarian cancer, wrote Liesel M. FitzGerald, PhD, of the University of Tasmania, Hobart, Australia, and colleagues in a Letter to the Editor in the European Journal of Cancer.

The L105X mutation was found via the ongoing Tasmanian Familial Prostate Cancer Study, which focuses on sizable families with long lineages in Tasmania and multiple cases of prostate cancer over several generations. In this particular “discovery” family, according to the authors, the mutation was found in seven individuals—four men with prostate cancer and three women with breast cancer—and “identity-by-descent analysis indicates that another three [individuals with] breast cancer are likely carriers.”

Not only is the L105X mutation rare, as indicated by the lack of a minor allele frequency listed in the Genome Aggregation Database, but it has a Combined Annotation Dependent Depletion score of 33. The score “indicates an extremely high level of predicted deleteriousness,” the investigators stated, adding that the significance of the mutation’s association with prostate cancer could be described as P = 5.00 x 10-7.

“Our study highlights the importance of determining a prostate cancer patient’s family history of other cancers in addition to prostate cancer,” stressed Dr. FitzGerald and co-investigators. The findings “support the call to extend germline genetic testing beyond metastatic patients and for its adoption in men with a strong family history of prostate cancer and/or breast cancer…to ensure that men who may benefit from PARP inhibitors or platinum-based chemotherapies do not continue to miss out on emerging and highly effective, gene-targeted therapies.”

Disclosure: The study authors reported no conflicts of interest.

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