title: Germline BAP1 inactivation is preferentially associated with metastatic ocular melanoma and cutaneous-ocular melanoma families.
abstract: BACKGROUND
  BAP1 has been shown to be a target of both somatic alteration in high-risk ocular melanomas (OM) and germline inactivation in a few individuals from cancer-prone families. These findings suggest that constitutional BAP1 changes may predispose individuals to metastatic OM and that familial permeation of deleterious alleles could delineate a new cancer syndrome.
  
  
  METHODS
  To characterize BAP1's contribution to melanoma risk, we sequenced BAP1 in a set of 100 patients with OM, including 50 metastatic OM cases and 50 matched non-metastatic OM controls, and 200 individuals with cutaneous melanoma (CM) including 7 CM patients from CM-OM families and 193 CM patients from CM-non-OM kindreds.
  
  
  RESULTS
  Germline BAP1 mutations were detected in 4/50 patients with metastatic OM and 0/50 cases of non-metastatic OM (8% vs. 0%, p = 0.059). Since 2/4 of the BAP1 carriers reported a family history of CM, we analyzed 200 additional hereditary CM patients and found mutations in 2/7 CM probands from CM-OM families and 1/193 probands from CM-non-OM kindreds (29% vs. 0.52%, p = .003). Germline mutations co-segregated with both CM and OM phenotypes and were associated with the presence of unique nevoid melanomas and highly atypical nevoid melanoma-like melanocytic proliferations (NEMMPs). Interestingly, 7/14 germline variants identified to date reside in C-terminus suggesting that the BRCA1 binding domain is important in cancer predisposition.
  
  
  CONCLUSIONS
  Germline BAP1 mutations are associated with a more aggressive OM phenotype and a recurrent phenotypic complex of cutaneous/ocular melanoma, atypical melanocytic proliferations and other internal neoplasms (ie. COMMON syndrome), which could be a useful clinical marker for constitutive BAP1 inactivation.
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Ching-Ni Jenny
authors.initials: CN
authors.lastname: Njauw
authors.forename: Ivana
authors.initials: I
authors.lastname: Kim
authors.forename: Adriano
authors.initials: A
authors.lastname: Piris
authors.forename: Michele
authors.initials: M
authors.lastname: Gabree
authors.forename: Michael
authors.initials: M
authors.lastname: Taylor
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Lane
authors.forename: Margaret M
authors.initials: MM
authors.lastname: DeAngelis
authors.forename: Evangelos
authors.initials: E
authors.lastname: Gragoudas
authors.forename: Lyn M
authors.initials: LM
authors.lastname: Duncan
authors.forename: Hensin
authors.initials: H
authors.lastname: Tsao
mesh_terms: D000328:Adult; D015331:Cohort Studies; D005123:Eye / Q000378:metabolism / Q000473:pathology; D005134:Eye Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000235:genetics*; D010375:Pedigree; D012867:Skin / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D043222:Ubiquitin Thiolesterase / Q000235:genetics*
chemical_list: C400134:BAP1 protein, human; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase