RESUMO
Polymorphisms of AIRE, a transcription factor that up-regulates intrathymic expression of tissue-specific antigens including melanoma-associated antigens (MAAs), may variably affect the selection of MAAs-specific thymocytes, generating T-cell repertoires protecting or predisposing individuals to melanoma. We found that AIRE single nucleotide polymorphisms (SNPs) rs1055311, rs1800520 and rs1800522 were significantly more frequent in healthy subjects than in melanoma patients, independently from sex, age and stages of melanoma. The presence of these SNPs was associated with increased frequency of two T-cell clonotypes specific for MAGE-1 linking their protective effect to selection/expansion of MAA-specific T cells. Interestingly, mRNA transcribed on the rs1800520 SNP showed increased free energy than the wild type suggesting that its reduced stability may be responsible for the different activity of the polymorphic AIRE molecule. This finding may contribute at identifying subjects with increased risk of developing melanoma or patients with melanoma that may take benefit from immunotherapy.
Assuntos
Melanoma/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Fatores Etários , Idoso , Antígenos de Neoplasias/genética , Feminino , Frequência do Gene/genética , Genes Codificadores da Cadeia beta de Receptores de Linfócitos T/genética , Genótipo , Heterozigoto , Homozigoto , Humanos , Masculino , Melanoma/diagnóstico , Antígenos Específicos de Melanoma , Pessoa de Meia-Idade , Modelos Moleculares , Proteínas de Neoplasias/genética , Conformação de Ácido Nucleico , Estabilidade de RNA/genética , RNA Mensageiro/química , RNA Mensageiro/genética , Caracteres Sexuais , Termodinâmica , Adulto Jovem , Proteína AIRERESUMO
Gorlin syndrome (GS) is inherited in an autosomal dominant pattern with high-penetrance and is characterized by a range of developmental anomalies and increased risk of developing basal cell carcinoma and medulloblastoma. Between 50% and 85% of patients with GS harbor germ line mutations in the only susceptibility gene identified to date, PTCH1, a key component in the Sonic Hedgehog signaling pathway. Another component in this pathway, SUFU, is known to be involved in susceptibility to medulloblastoma but has never been reported in GS patients to date. We have identified the known c.1022 + 1G>A SUFU germ line splicing mutation in a family that was PTCH1-negative and who had signs and symptoms of GS, including medulloblastoma. This is the first report of a germ line SUFU mutation associated with GS.
Assuntos
Síndrome do Nevo Basocelular/genética , Mutação em Linhagem Germinativa , Proteínas Repressoras/genética , Adulto , Síndrome do Nevo Basocelular/diagnóstico , Sequência de Bases , Pré-Escolar , Família , Feminino , Humanos , Receptores Patched , Receptor Patched-1 , Receptores de Superfície Celular/genéticaRESUMO
BACKGROUND: Diagnosis of Nevoid Basal Cell Carcinoma Syndrome (NBCCS) in infants may pose significant challenges to clinicians owing to its variable expressivity and age-related manifestations. METHODS: We report two paediatric cases of NBCCS who presented initially with a non-specific phenotype. RESULTS: In case 1, a diagnosis of NBCCS was possible only after the father was interviewed and found to present with two major criteria for the disease. Subsequent molecular testing confirmed the diagnosis. In case 2, molecular testing of the infant and his father had diagnostic value as neither satisfied fully the current diagnostic criteria for NBCCS. CONCLUSIONS: Presence of the few clinical manifestations of NBCCS that appear in infants, typically congenital malformations and skeletal abnormalities, should prompt clinicians to conduct in-person interviews with both parents. In general, paediatricians should refer both parents of infants who are suspected of having an inherited condition to clinical geneticists for expert examination, given the potential unreliability of reported medical history.