title: Novel and recurrent germline and somatic mutations in a cohort of 67 patients from 48 families with Brooke-Spiegler syndrome including the phenotypic variant of multiple familial trichoepitheliomas and correlation with the histopathologic findings in 379 biopsy specimens.
abstract: Brooke-Spiegler syndrome (BSS) is a rare, inherited, autosomal dominant disorder characterized by development of multiple adnexal cutaneous neoplasms including spiradenoma, cylindroma, spiradenocylindroma, and trichoepithelioma. The syndrome of multiple familial trichoepitheliomas (MFT) is considered a phenotypic variant of BSS in which patients present with trichoepitheliomas only. We studied germline and somatic mutations of the CYLD gene by direct sequencing in patients with BSS (n = 49) and MFT (n = 18) using peripheral blood and 90 samples of frozen or formalin-fixed paraffin-embedded tumor tissue selected from 379 available histology specimens. Germline CYLD mutations were found in 51 patients (76%) from 36 families (75%). Germline CYLD mutations were found in 43 of the 49 patients with BSS (88%) but in only 8 of 18 MFT cohort (44%). Twenty-one frameshift, 15 nonsense, 3 missense, and 4 splice site mutations were found in patients with BSS, whereas 1 frameshift, 5 nonsense, and 2 splice site mutations were identified in the MFT cohort. Five novel mutations were identified including 4 frameshift mutations (c.1027dupA/p.T343NfsX7, c.2155dupA/p.M719NfsX5, c.2288_2289delTT/p.F763X, and c.2641delG/p.D881TfsX32) and 1 nonsense mutation (c.2713C>T/p. Q905X). Of the 76 tumors from 32 patients with a germline CYLD mutation, 12 were spiradenomas, 15 spiradenocylindromas, 26 cylindromas, 15 trichoepitheliomas, and 7 were other tumor types. Somatic mutations were detected in 67 specimens of these 76 tumors (88%). Of the 67 somatic mutations, 21 (31%) represented a sequence alteration and 46 (69%) showed loss of heterozygosity. In the remaining 9 cases (12%), the somatic changes remained unknown. A germline CYLD mutation was not detected in 14 tumor samples from 8 patients. In these 14 tumors, somatic mutations were identified in 6 samples (43%), all consisting of sequence alterations (1 sample showed 2 different sequence alterations). In the remaining 8 samples (53%), neither germline nor somatic mutations were found in the lesional tissue. Our study increases the catalog of known CYLD mutations in patients with BSS/MFT to 86 and documents the variability of somatic mutations that may occur in them. We confirm the absence of firm genotype-phenotype correlations and the existence of a subset of patients with BSS/MFT who lack a demonstrable germline CYLD mutation. Further studies are needed to explain the reasons for this phenomenon.
authors.affiliation: Bioptical Laboratory, Pilsen, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Grossmann
authors.forename: Tomas
authors.initials: T
authors.lastname: Vanecek
authors.forename: Petr
authors.initials: P
authors.lastname: Steiner
authors.forename: Denisa
authors.initials: D
authors.lastname: Kacerovska
authors.forename: Dominic V
authors.initials: DV
authors.lastname: Spagnolo
authors.forename: Bernard
authors.initials: B
authors.lastname: Cribier
authors.forename: Christian
authors.initials: C
authors.lastname: Rose
authors.forename: Marina
authors.initials: M
authors.lastname: Vazmitel
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Carlson
authors.forename: Michael
authors.initials: M
authors.lastname: Emberger
authors.forename: Petr
authors.initials: P
authors.lastname: Martinek
authors.forename: Robert L
authors.initials: RL
authors.lastname: Pearce
authors.forename: John
authors.initials: J
authors.lastname: Pearn
authors.forename: Michal
authors.initials: M
authors.lastname: Michal
authors.forename: Dmitry V
authors.initials: DV
authors.lastname: Kazakov
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D000074749:Deubiquitinating Enzyme CYLD; D005260:Female; D016368:Frameshift Mutation; D005629:Frozen Sections; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics* / Q000473:pathology*; D016612:Paraffin Embedding; D010375:Pedigree; D010641:Phenotype; D012867:Skin / Q000473:pathology*; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D018389:Codon, Nonsense; D025521:Tumor Suppressor Proteins; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD