title: Mesothelioma families without inheritance of a BAP1 predisposing mutation.
abstract: Familial malignant mesothelioma clusters are ideal candidates to explore BAP1 genomic status as a predisposing risk factor. We report data on BAP1 analysis in four families with multiple mesothelioma cases to investigate possible BAP1 alterations associated with an inherited cancer syndrome. We also recorded family history of cancer and assessed asbestos exposure. By genomic direct sequencing, we found no evidence of a BAP1 germline mutation in tumor DNA samples (one mesothelioma per family: n = 3 epithelioid; n = 1 biphasic). On the other hand, we identified a novel BAP1 somatic alteration (c.329_335delinsTC) in exon 5 (n = 1 biphasic), and we hypothesized the occurrence of somatic inactivating events not identifiable by sequencing in the other cases (n = 3 epithelioid), as demonstrated by the loss of nuclear BAP1 immunostaining. History of other cancers was in sites not typical of the BAP1 cancer syndrome. Asbestos exposure was occupational (n = 2 clusters), household (n = 1), and unknown (n = 1). These family units without inheritance of a BAP1 predisposing mutation expand the number of unmutated germline BAP1 families with multiple mesothelioma cases. This suggests that besides the exposure to asbestos other currently unknown genetic or epigenetic factors may be responsible for the high incidence of mesothelioma in BAP1-unmutated families.
authors.affiliation: Department of Radiological, Oncological and Anatomo-Pathological Sciences, Sapienza University, Viale Regina, 324-00161 Rome, Italy. Electronic address: valeria.ascoli@uniroma1.it.
authors.forename: Valeria
authors.initials: V
authors.lastname: Ascoli
authors.affiliation: Department of Radiological, Oncological and Anatomo-Pathological Sciences, Sapienza University, Viale Regina, 324-00161 Rome, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Cozzi
authors.affiliation: Department of Oncology, San Luigi Hospital, University of Turin, Regione Gonzole, 10-10043 Orbassano, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Vatrano
authors.affiliation: Department of Oncology, San Luigi Hospital, University of Turin, Regione Gonzole, 10-10043 Orbassano, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Izzo
authors.affiliation: Department of Oncology, San Luigi Hospital, University of Turin, Regione Gonzole, 10-10043 Orbassano, Italy.
authors.forename: Jessica
authors.initials: J
authors.lastname: Giorcelli
authors.affiliation: Department of Epidemiology, Lazio Regional Health Service, Via Cristoforo Colombo, 112-00147 Rome, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Romeo
authors.affiliation: Department of Epidemiology, Lazio Regional Health Service, Via Cristoforo Colombo, 112-00147 Rome, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Carnovale-Scalzo
authors.affiliation: Department of Pathology, San Camillo Hospital, Circonvallazione Gianicolense, 87-00152 Rome, Italy.
authors.forename: Lucia Rosalba
authors.initials: LR
authors.lastname: Grillo
authors.affiliation: Department of Oncologic Thoracic Surgery, Regina Elena Cancer Institute, Via Elio Chianesi, 53-00144 Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Facciolo
authors.affiliation: Department of Pathology, Regina Elena Cancer Institute, Via Elio Chianesi, 53-00144 Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Visca
authors.affiliation: Department of Oncology, Pathology Unit, AOU Città della Salute e della Scienza, University of Turin, Corso Bramante, 88-10126 Turin, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Papotti
authors.affiliation: Department of Oncology, San Luigi Hospital, University of Turin, Regione Gonzole, 10-10043 Orbassano, Italy.
authors.forename: Luisella
authors.initials: L
authors.lastname: Righi
mesh_terms: D000368:Aged; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D043222:Ubiquitin Thiolesterase / Q000235:genetics*
chemical_list: C400134:BAP1 protein, human; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase
keywords: BAP1 germline mutation; BAP1 somatic mutation; Malignant mesothelioma; asbestos; familial cancer