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.

Morphologically low-grade spiradenocarcinoma: a clinicopathologic study of 19 cases with emphasis on outcome and MYB expression

“…Both may be observed in patients with the BrookeSpiegler syndrome, and occasionally hybrid tumors with features of both spiradenoma and cylindroma are encountered. 24 Furthermore, malignant transformation has been documented in spiradenoma, cylindroma, and hybrid tumors. 1,2 Recently, a genetic link has also been established between dermal cylindroma and adenoid cystic carcinoma with both tumors sharing the t(6;9) translocation involving MYB and NFIB, resulting in MYB overexpression detectable by immunohistochemistry.…”

Phenotype–genotype correlations for clinical variants caused by CYLD mutations

“…Pedigree II contains 21 affected family members from seven generations, all of whom exhibit severe symptoms also located on their scalp, middle face and trunk [Grossmann et al, 2013].…”

“…BSS, FC and MFT1 were originally described as distinct clinical entities, but due to their overlapping clinical symptoms and their manifestation within the same families, they are now considered as a clinical variants that represent a phenotypic spectrum of a single entity Welch et al, 1968;Young et al, 2006;Oranje et al, 2008]. [Bignell et al, 2000;Bowen et al, 2005;Grossmann et al, 2013;Linos et al, 2011;Lv et al, 2008;Kacerovska et al, 2013;Saggar et al, 2008;Van den Ouweland et al, 2011;Oiso et al, 2004;Zhang et al, 2006;Kazakov et al, 2009;Kazakov et al, 2011;Nagy et al, 2013]. Therefore, it has been hypothesized that BSS, FC and MFT1 are not different disease entities, but represent a phenotypic spectrum of the same disease.…”

Germline mutation analysis in the CYLD gene in Chinese patients with multiple trichoepitheliomas

“…Vorechovský et al (1997) reported 2 cases with frameshift mutations and in-frame somatic deletions in the CYLD gene. Somatic mutations were detected in 2 and 3 of the 7 and 10 cases lacking germline CYLD mutations, respectively, as reported by Kazakov et al (2011) andGrossmann (2013). However, equally important is that trichoepitheliomas displays genetic heterogeneity and may thus contain gene abnormalities other than those in CYLD, such as some CYLD-regulating genes that may map to the undetermined 9q21 or 9p22 regions.…”

“…Ponti et al (2012) reported an MFT patient without abnormalities in CYLD. Saggar et al (2008), Kazakov et al (2011), and Grossmann et al (2013) reported 9, 13, and 18 MFT patients, respectively, in which a germline mutation in CYLD was found in only 4 (44.4%), 6 (46%), and 8 (44.4%) cases, respectively. There have been few studies examining multiple trichoepitheliomas without a family history.…”