RESUMEN
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.
Asunto(s)
Mutación , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Piel/patología , Proteínas Supresoras de Tumor/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Codón sin Sentido , Análisis Mutacional de ADN , Enzima Desubiquitinante CYLD , Femenino , Mutación del Sistema de Lectura , Secciones por Congelación , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Humanos , Pérdida de Heterocigocidad , Masculino , Persona de Mediana Edad , Mutación Missense , Adhesión en Parafina , Linaje , Fenotipo , Adulto JovenRESUMEN
Brooke-Spiegler syndrome (BSS) is an inherited autosomal dominant disease characterized by the development of multiple adnexal cutaneous neoplasms including spiradenoma, cylindroma, spiradenocylindroma, and trichoepithelioma (cribriform trichoblastoma). BSS patients have various mutations in the CYLD gene, a tumor suppressor gene located on chromosome 16q. Our search of the literature revealed 51 germline CYLD mutations reported to date. Somatic CYLD mutations have rarely been investigated. We studied 10 patients from 8 families with BSS. Analysis of germline mutations of the CYLD gene was performed using either peripheral blood or nontumorous tissue. In addition, 19 formalin-fixed paraffin-embedded tumor samples were analyzed for somatic mutations, including loss of heterozygosity studies. A total of 38 tumors were available for histopathologic review. We have identified 8 novel germline mutations, all of which consisted of substitutions, deletions, and insertions/duplications and all except one led to premature stop codons. The substitution mutation in a single case was also predicted to disrupt protein function and seems causally implicated in tumor formation. We demonstrate for the first time that somatic events, loss of heterozygosity, or sequence mutations may differ among multiple neoplasms even of the same histologic type, occurring in the same patient.
Asunto(s)
Trastornos de los Cromosomas , Mutación de Línea Germinal , Neoplasias Cutáneas/genética , Proteínas Supresoras de Tumor/genética , Adulto , Anciano , Codón sin Sentido , Técnicas Citológicas/métodos , Enzima Desubiquitinante CYLD , Salud de la Familia , Heterocigoto , Humanos , Mutación INDEL , Masculino , Persona de Mediana Edad , Mutación Missense , Patología Molecular/métodos , Adulto JovenRESUMEN
Of all skin cancers, cutaneous malignant melanoma (CMM) is the most aggressive and the life expectancy of patients with lymphatic or systemic metastases is dramatically reduced. Understandably therefore, scientists and clinicians have focused on improving diagnostic and prognostic techniques. Of these, perhaps the most promising are multimarker real-time RT-PCR and microarray for detection of circulating CMM cells in peripheral blood. While the optimal set of markers is still to be identified that can accurately assess disease severity and progression at all clinical stages of the disease, recent progress has been dramatic. Here we provide an exhaustive review of recent studies in which a variety of markers are assessed. Moreover, the efficacy of the markers relative to clinical stage is discussed in light of experimental findings. From these studies, it is apparent that researchers are now much closer to defining a set of markers of circulating cells that can be utilized in routine diagnostic tests.