title: BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs.
abstract: BACKGROUND
  BRCA1-associated protein 1 (BAP1) is a tumor suppressor gene located on chromosome 3p21. Germline BAP1 mutations have been recently associated with an increased risk of malignant mesothelioma, atypical melanocytic tumors and other neoplasms. To answer the question if different germline BAP1 mutations may predispose to a single syndrome with a wide phenotypic range or to distinct syndromes, we investigated the presence of melanocytic tumors in two unrelated families (L and W) with germline BAP1 mutations and increased risk of malignant mesothelioma.
  
  
  METHODS
  Suspicious cutaneous lesions were clinically and pathologically characterized and compared to those present in other families carrying BAP1 mutations. We then conducted a meta-analysis of all the studies reporting BAP1-mutated families to survey cancer risk related to the germline BAP1 mutation (means were compared using t-test and proportions were compared with Pearson χ2 test or two-tailed Fisher's exact test).
  
  
  RESULTS
  Melanocytic tumors: of the five members of the L family studied, four (80%) carried a germline BAP1 mutation (p.Gln684*) and also presented one or more atypical melanocytic tumors; of the seven members of W family studied, all carried a germline BAP1 mutation (p.Pro147fs*48) and four of them (57%) presented one or more atypical melanocytic tumors, that we propose to call "melanocytic BAP1-mutated atypical intradermal tumors" (MBAITs). Meta-analysis: 118 individuals from seven unrelated families were selected and divided into a BAP1-mutated cohort and a BAP1-non-mutated cohort. Malignant mesothelioma, uveal melanoma, cutaneous melanoma, and MBAITs prevalence was significantly higher in the BAP1-mutated cohort (p ≤ 0.001).
  
  
  CONCLUSIONS
  Germline BAP1 mutations are associated with a novel cancer syndrome characterized by malignant mesothelioma, uveal melanoma, cutaneous melanoma and MBAITs, and possibly by other cancers. MBAITs provide physicians with a marker to identify individuals who may carry germline BAP1 mutations and thus are at high risk of developing associated cancers.
authors.affiliation: University of Hawai'i Cancer Center, 677 Ala Moana Boulevard, Suite 901, Honolulu, HI 96813, USA. mcarbone@cc.hawaii.edu
authors.forename: Michele
authors.initials: M
authors.lastname: Carbone
authors.forename: Laura Korb
authors.initials: LK
authors.lastname: Ferris
authors.forename: Francine
authors.initials: F
authors.lastname: Baumann
authors.forename: Andrea
authors.initials: A
authors.lastname: Napolitano
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Lum
authors.forename: Erin G
authors.initials: EG
authors.lastname: Flores
authors.forename: Giovanni
authors.initials: G
authors.lastname: Gaudino
authors.forename: Amy
authors.initials: A
authors.lastname: Powers
authors.forename: Peter
authors.initials: P
authors.lastname: Bryant-Greenwood
authors.forename: Thomas
authors.initials: T
authors.lastname: Krausz
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hyjek
authors.forename: Rachael
authors.initials: R
authors.lastname: Tate
authors.forename: Joseph
authors.initials: J
authors.lastname: Friedberg
authors.forename: Tracey
authors.initials: T
authors.lastname: Weigel
authors.forename: Harvey I
authors.initials: HI
authors.lastname: Pass
authors.forename: Haining
authors.initials: H
authors.lastname: Yang
mesh_terms: D015331:Cohort Studies; D006801:Humans; D008545:Melanoma / Q000503:physiopathology*; D008654:Mesothelioma / Q000503:physiopathology*; D012878:Skin Neoplasms / Q000503:physiopathology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D043222:Ubiquitin Thiolesterase / Q000502:physiology*; D014604:Uveal Neoplasms / Q000503:physiopathology*
chemical_list: C400134:BAP1 protein, human; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase