RESUMEN
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.
Asunto(s)
Antígenos CD28/genética , Carcinoma de Células Escamosas/genética , Epistasis Genética , Predisposición Genética a la Enfermedad , Interferón gamma/genética , Neoplasias del Cuello Uterino/genética , Brasil , Estudios de Casos y Controles , Femenino , HumanosRESUMEN
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.
Asunto(s)
Adenocarcinoma/enzimología , Carcinoma de Células Escamosas/enzimología , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Granzimas/análisis , Neoplasias del Cuello Uterino/enzimología , Adenocarcinoma/genética , Adenocarcinoma/inmunología , Adenocarcinoma/patología , Adenocarcinoma/terapia , Adulto , Anciano , Antígenos CD/análisis , Antígenos de Diferenciación de Linfocitos T/análisis , Antígeno B7-1/análisis , Antígeno B7-2/análisis , Antígenos CD28/análisis , Antígeno CTLA-4 , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/terapia , Femenino , Granzimas/genética , Humanos , Ligando Coestimulador de Linfocitos T Inducibles , Proteína Coestimuladora de Linfocitos T Inducibles , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , ARN Mensajero/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo , Resultado del Tratamiento , Regulación hacia Arriba , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/inmunología , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/terapiaRESUMEN
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.