RESUMO
Genetic mapping studies have identified multiple cancer susceptibility regions at chromosome 8q24, upstream of the MYC oncogene. MYC has been widely presumed as the regulated target gene, but definitive evidence functionally linking these cancer regions with MYC has been difficult to obtain. Here we examined candidate functional variants of a haplotype block at 8q24 encompassing the two independent risk alleles for prostate and breast cancer, rs620861 and rs13281615. We used the mapping of DNase I hypersensitive sites as a tool to prioritise regions for further functional analysis. This approach identified rs378854, which is in complete linkage disequilibrium (LD) with rs620861, as a novel functional prostate cancer-specific genetic variant. We demonstrate that the risk allele (G) of rs378854 reduces binding of the transcription factor YY1 in vitro. This factor is known to repress global transcription in prostate cancer and is a candidate tumour suppressor. Additional experiments showed that the YY1 binding site is occupied in vivo in prostate cancer, but not breast cancer cells, consistent with the observed cancer-specific effects of this single nucleotide polymorphism (SNP). Using chromatin conformation capture (3C) experiments, we found that the region surrounding rs378854 interacts with the MYC and PVT1 promoters. Moreover, expression of the PVT1 oncogene in normal prostate tissue increased with the presence of the risk allele of rs378854, while expression of MYC was not affected. In conclusion, we identified a new functional prostate cancer risk variant at the 8q24 locus, rs378854 allele G, that reduces binding of the YY1 protein and is associated with increased expression of PVT1 located 0.5 Mb downstream.
Assuntos
Cromossomos Humanos Par 8/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Neoplasias da Próstata/genética , RNA não Traduzido/genética , Alelos , Sequência de Bases , Sítios de Ligação/genética , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Sequência Consenso , Feminino , Regulação Neoplásica da Expressão Gênica , Genótipo , Células HCT116 , Humanos , Masculino , Modelos Biológicos , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/patologia , RNA não Traduzido/metabolismo , Ativação Transcricional/genética , Fator de Transcrição YY1/metabolismoRESUMO
BACKGROUND: Lichen planus is an autoimmune, inflammatory dermatosis of unknown cause that affects the skin and mucous membranes. OBJECTIVE: The aim of this study was to report the clinical features and response to therapy in a series of patients with ocular lichen planus. METHODS: A retrospective chart review was performed to identify patients with ocular lichen planus. Information about clinical presentation, treatment, and therapeutic response was extracted from the medical records. RESULTS: Eleven patients with ocular lichen planus were identified. The diagnosis was confirmed histologically for 10 patients. Nine patients were women. The average time from onset of ocular symptoms to diagnosis was 4.1 years. Eight patients had mucous membrane involvement at other sites. Disease was well controlled in eight patients. CONCLUSION: Lichen planus should be considered in the differential diagnosis of cicatricial conjunctivitis, especially when severe lichen planus is noted at other sites.