RESUMO
Although human papillomavirus was identified as an aetiological factor in cervical cancer, the key human gene drivers of this disease remain unknown. Here we apply an unbiased approach integrating gene expression and chromosomal aberration data. In an independent group of patients, we reconstruct and validate a gene regulatory meta-network, and identify cell cycle and antiviral genes that constitute two major subnetworks upregulated in tumour samples. These genes are located within the same regions as chromosomal amplifications, most frequently on 3q. We propose a model in which selected chromosomal gains drive activation of antiviral genes contributing to episomal virus elimination, which synergizes with cell cycle dysregulation. These findings may help to explain the paradox of episomal human papillomavirus decline in women with invasive cancer who were previously unable to clear the virus.
Assuntos
Antivirais/metabolismo , Ciclo Celular/genética , Redes Reguladoras de Genes/genética , Genes Neoplásicos/genética , Papillomaviridae/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/virologia , Aberrações Cromossômicas , Cromossomos Humanos/genética , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genoma Humano/genética , Instabilidade Genômica , Humanos , Proteínas de Membrana Lisossomal/metabolismo , Metanálise como Assunto , Proteínas de Neoplasias/metabolismo , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/virologia , Reprodutibilidade dos Testes , Neoplasias do Colo do Útero/patologia , Integração Viral/genéticaRESUMO
The present study assessed, in cervical carcinoma, expression levels of seven immune response genes and sought correlation to response to treatment. The expression levels of CD28, CTLA4, ICOS, ICOSL, CD80 and CD86 and granzyme B genes were assessed by real-time RT-PCR in pre-treatment tumor fragments. During the six-month follow-up after treatment, 8 patients presented tumor and 10 survived free of tumor. The only gene whose expression levels were higher in patients with poor outcome (p = 0.03) was granzyme B. Further evaluation, in adequately powered prospective studies is warranted to confirm the data and to translate this observation to the clinical setting.
Assuntos
Adenocarcinoma/enzimologia , Carcinoma de Células Escamosas/enzimologia , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Granzimas/análise , Neoplasias do Colo do Útero/enzimologia , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Adulto , Idoso , Antígenos CD/análise , Antígenos de Diferenciação de Linfócitos T/análise , Antígeno B7-1/análise , Antígeno B7-2/análise , Antígenos CD28/análise , Antígeno CTLA-4 , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Feminino , Granzimas/genética , Humanos , Ligante Coestimulador de Linfócitos T Induzíveis , Proteína Coestimuladora de Linfócitos T Induzíveis , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Resultado do Tratamento , Regulação para Cima , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/terapiaRESUMO
Cervical cancer is a complex disease with multiple environmental and genetic determinants. In this study, we sought an association between polymorphisms in immune response genes and cervical cancer using both single-locus and multi-locus analysis approaches. A total of 14 single nucleotide polymorphisms (SNPs) distributed in CD28, CTLA4, ICOS, PDCD1, FAS, TNFA, IL6, IFNG, TGFB1 and IL10 genes were determined in patients and healthy individuals from three independent case/control sets. The first two sets comprised White individuals (one group with 82 cases and 85 controls, the other with 83 cases and 85 controls) and the third was constituted by non-white individuals (64 cases and 75 controls). The multi-locus analysis revealed higher frequencies in cancer patients of three three-genotype combinations [CD28+17(TT)/IFNG+874(AA)/TNFA-308(GG), CD28+17(TT)/IFN+847(AA)/PDCD1+7785(CT), and CD28 +17(TT)/IFNG+874(AA)/ICOS+1564(TT)] (P < 0.01, Monte Carlo simulation). We hypothesized that this two-genotype [CD28(TT) and IFNG(AA)] combination could have a major contribution to the observed association. To address this question, we analyzed the frequency of the CD28(TT), IFNG(AA) genotype combination in the three groups combined, and observed its increase in patients (P = 0.0011 by Fisher's exact test). The contribution of a third polymorphism did not reach statistical significance (P = 0.1). Further analysis suggested that gene-gene interaction between CD28 and IFNG might contribute to susceptibility to cervical cancer. Our results showed an epistatic effect between CD28 and IFNG genes in susceptibility to cervical cancer, a finding that might be relevant for a better understanding of the disease pathogenesis. In addition, the novel analytical approach herein proposed might be useful for increasing the statistical power of future genome-wide multi-locus studies.