Abstract
We recently discovered an inherited cancer syndrome caused by BRCA1-Associated Protein 1 (BAP1) germline mutations, with high incidence of mesothelioma, uveal melanoma and other cancers and very high penetrance by age 55. To identify families with the BAP1 cancer syndrome, we screened patients with family histories of multiple mesotheliomas and melanomas and/or multiple cancers. We identified four families that shared an identical BAP1 mutation: they lived across the US and did not appear to be related. By combining family histories, molecular genetics, and genealogical approaches, we uncovered a BAP1 cancer syndrome kindred of ~80,000 descendants with a core of 106 individuals, whose members descend from a couple born in Germany in the early 1700s who immigrated to North America. Their descendants spread throughout the country with mutation carriers affected by multiple malignancies. Our data show that, once a proband is identified, extended analyses of these kindreds, using genomic and genealogical studies to identify the most recent common ancestor, allow investigators to uncover additional branches of the family that may carry BAP1 mutations. Using this knowledge, we have identified new branches of this family carrying BAP1 mutations. We have also implemented early-detection strategies that help identify cancers at early-stage, when they can be cured (melanomas) or are more susceptible to therapy (MM and other malignancies).
Highlights
Malignant mesothelioma (MM) is frequent in individuals who are heavily exposed to asbestos and/or other mineral fibers [1]
Germline BRCA1-Associated Protein 1 (BAP1) mutations cause a cancer syndrome characterized by high incidence of mesothelioma (MM), uveal melanoma and other cancers, and by very high penetrance, as all individuals carrying BAP1 mutations developed at least one, and usually several, malignancies throughout their lives
We investigated whether this BAP1 mutation occurred in a ‘hot-spot’ for “de novo” mutations or whether these four MM patients shared a common ancestor
Summary
Malignant mesothelioma (MM) is frequent (up to 5% prevalence) in individuals who are heavily exposed to asbestos and/or other mineral fibers [1]. In subsequent studies in US families with high incidence of MM and of uveal melanoma (UM) and no apparent exposure to mineral fibers, we identified germline mutations in the BAP1 gene, as the major risk factor for MM and UM development [3]. Thereafter, we and others confirmed that germline BAP1 mutations are a common heritable factor that predispose to MM, UM, cutaneous melanoma (CM), cholangiocarcinoma, renal cell carcinoma (RCC), and basal cell carcinoma (BCC) [4,5,6], and to benign atypical melanocytic lesions known as MBAITs [7, 8], and likely to several other malignancies including brain, breast, lung cancer, and sarcomas [9],—recently grouped together into the “BAP1 cancer syndrome” [7]. There is, a preponderance of MMs and melanomas [7]
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