title: Combined Genetic and Genealogic Studies Uncover a Large BAP1 Cancer Syndrome Kindred Tracing Back Nine Generations to a Common Ancestor from the 1700s.
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).
authors.affiliation: Thoracic Oncology Program, University of Hawai'i Cancer Center, Honolulu, Hawai'i, United States of America.
authors.forename: Michele
authors.initials: M
authors.lastname: Carbone
authors.affiliation: Thoracic Oncology Program, University of Hawai'i Cancer Center, Honolulu, Hawai'i, United States of America.
authors.forename: Erin G
authors.initials: EG
authors.lastname: Flores
authors.affiliation: Thoracic Oncology Program, University of Hawai'i Cancer Center, Honolulu, Hawai'i, United States of America.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Emi
authors.affiliation: Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama City, Kanagawa, Japan.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Johnson
authors.affiliation: Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama City, Kanagawa, Japan.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tsunoda
authors.affiliation: Thoracic Oncology Program, University of Hawai'i Cancer Center, Honolulu, Hawai'i, United States of America.
authors.forename: Dusty
authors.initials: D
authors.lastname: Behner
authors.affiliation: Genealogy from the Hart, Honolulu, Hawai'i, United States of America.
authors.forename: Harriet
authors.initials: H
authors.lastname: Hoffman
authors.affiliation: Mesothelioma Applied Research Foundation, Alexandria, Virginia, United States of America.
authors.forename: Mary
authors.initials: M
authors.lastname: Hesdorffer
authors.affiliation: Thoracic Oncology Program, University of Hawai'i Cancer Center, Honolulu, Hawai'i, United States of America.
authors.forename: Masaki
authors.initials: M
authors.lastname: Nasu
authors.affiliation: Thoracic Oncology Program, University of Hawai'i Cancer Center, Honolulu, Hawai'i, United States of America.
authors.forename: Andrea
authors.initials: A
authors.lastname: Napolitano
authors.affiliation: Thoracic Oncology Program, University of Hawai'i Cancer Center, Honolulu, Hawai'i, United States of America.
authors.forename: Amy
authors.initials: A
authors.lastname: Powers
authors.affiliation: Thoracic Oncology Program, University of Hawai'i Cancer Center, Honolulu, Hawai'i, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Minaai
authors.affiliation: Thoracic Oncology Program, University of Hawai'i Cancer Center, Honolulu, Hawai'i, United States of America.
authors.forename: Francine
authors.initials: F
authors.lastname: Baumann
authors.affiliation: Thoracic Oncology Program, University of Hawai'i Cancer Center, Honolulu, Hawai'i, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Bryant-Greenwood
authors.affiliation: Klinik für Thoraxchirurgie Universitätsspital, Zürich, Switzerland.
authors.forename: Olivia
authors.initials: O
authors.lastname: Lauk
authors.affiliation: Klinik für Thoraxchirurgie Universitätsspital, Zürich, Switzerland.
authors.forename: Michaela B
authors.initials: MB
authors.lastname: Kirschner
authors.affiliation: Klinik für Thoraxchirurgie Universitätsspital, Zürich, Switzerland.
authors.forename: Walter
authors.initials: W
authors.lastname: Weder
authors.affiliation: Klinik für Thoraxchirurgie Universitätsspital, Zürich, Switzerland.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Opitz
authors.affiliation: Department of Cardiothoracic Surgery, New York University Langone Medical Center, New York, New York, United States of America.
authors.forename: Harvey I
authors.initials: HI
authors.lastname: Pass
authors.affiliation: Thoracic Oncology Program, University of Hawai'i Cancer Center, Honolulu, Hawai'i, United States of America.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Gaudino
authors.affiliation: Thoracic Oncology Program, University of Hawai'i Cancer Center, Honolulu, Hawai'i, United States of America.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pastorino
authors.affiliation: Thoracic Oncology Program, University of Hawai'i Cancer Center, Honolulu, Hawai'i, United States of America.
authors.forename: Haining
authors.initials: H
authors.lastname: Yang
mesh_terms: D005260:Female; D005789:Genealogy and Heraldry; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D005858:Germany; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008654:Mesothelioma / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D043222:Ubiquitin Thiolesterase / Q000235:genetics*; D014481:United States; D014604:Uveal Neoplasms / Q000235:genetics* / Q000473:pathology; D000098943:Uveal Melanoma
chemical_list: C400134:BAP1 protein, human; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase