Mesothelioma-associated BAP1 Mutation Found in Four Related Families

Mesothelioma-associated BAP1 Mutation Found in Four Related Families

In a new study, researchers from the University of Hawaii identified an inherited cancer syndrome known to be associated with high incidence of mesothelioma, uveal melanoma, and other cancers. The discovery was made by studying molecular genetics, familial history, and genealogical studies of four families that shared the same BRCA1-Associated Protein 1 (BAP1). The research paper, entitled “Combined Genetic and Genealogic Studies Uncover a Large BAP1 Cancer Syndrome Kindred Tracing Back Nine Generations to a Common Ancestor from the 1700s,” was published in PLOS Genetics.

BRCA1-associated protein 1 (BAP1) is a tumor suppressor gene whose function helps regulate vital cellular processes and pathways, such as DNA replication, transcription and response to DNA damage. Several studies have associated germline BAP1 mutations with a cancer syndrome, characterized by an increased risk for malignant mesothelioma, uveal melanoma, cutaneous melanoma and other cancers. Besides the high incidence of these cancers, individuals carrying BAP1 mutations develop at least one malignancy throughout the course of their lives, making the early detection of such mutations extremely important for patient survival.

In order to identify families with the BAP1 cancer syndrome, the researchers screened patients with histories of malignant mesothelioma and/or other multiple cancers. Four families supposedly unrelated and living in different U.S. states were identified as having an identical germline BAP1 mutation. The scientists formulated two hypothesis for this occurrence: either the researchers had identified a hot spot for “de novo” mutations or the 4 families shared a common ancestor and were related. Using molecular genetic techniques, the researchers discovered that they were indeed related. Combining these findings with familial histories and genealogic studies, the scientists traced their common ancestor to a couple born in Germany in the early 1700s that had immigrated to North America and whose descendants had migrated throughout America and were found, in the present era, in at least three different US states.

The results showed that the mutations were transmitted across several generations, with a family tree comprising ~80,000 descendants. This approach shows that such analyses can identify additional unknown parts of these families that may carry BAP1 mutations and, consequently, will allow at-risk individuals to be tested for the inherited mutation.

The researchers concluded that “Our study shows that the application of modern genomic analyses, coupled with “classical” family histories collected by the treating physician, and with genealogical searches, offer a powerful strategy to identify high-risk germline BAP1 mutation carriers that will benefit from genetic counseling and early detection cancer screening.”

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Margarida graduated with a BS in Health Sciences from the University of Lisbon and a MSc in Biotechnology from Instituto Superior Técnico (IST-UL). She worked as a molecular biologist research associate at a Cambridge UK-based biotech company that discovers and develops therapeutic, fully human monoclonal antibodies.

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