RESUMEN
BACKGROUND: Infection with human papillomavirus (HPV) is the main cause of cervical cancer and its precursor lesion, cervical intraepithelial neoplasia (CIN). Variability in host immunogenetic background is important in determining the overall cellular immune response to HPV infections. OBJECTIVE: To determine whether the HLA-DQ or HLA-DR genes, or others in their vicinity, are associated with cervical cancer. METHODS: Markers covering the entire HLA region were genotyped in a large sample of CIN and cervical cancer patients and in controls (311 CIN, 695 cervical cancer, 115 family controls, and 586 unrelated controls). RESULTS: Two markers were associated with susceptibility to cervical neoplasia, G511525 and MICA. G511525, close to the region containing the HLA-DQ and HLA-DR genes, was most strongly associated, showing a decrease in frequency of allele 221 from 6.7% to 3.3% in patients with squamous cell cancer (SCC). An association was found for MICA (allele 184) with SCC (odds ratio (OR) = 1.31 (95% confidence interval, 1.13 to 1.53); homozygotes, OR = 1.48 (1.06 to 2.06)). No associations were observed with adenocarcinoma or CIN. CONCLUSIONS: There is an association of the region containing the HLA-DQ and HLA-DR genes with the risk of developing squamous cell carcinoma. An increased risk was observed for carriers of allele 184 at the MICA locus, in particular for homozygotes, suggesting a recessive effect.
Asunto(s)
Carcinoma de Células Escamosas/genética , Predisposición Genética a la Enfermedad/genética , Antígenos HLA/genética , Neoplasias del Cuello Uterino/genética , Adenocarcinoma/genética , Femenino , Efecto Fundador , Frecuencia de los Genes , Marcadores Genéticos , Genotipo , Humanos , Polimorfismo de Nucleótido Simple , Displasia del Cuello del Útero/genéticaRESUMEN
Infection with oncogenic types of human papillomavirus (HPV) is the main causal factor of cervical cancer and its precursor lesion (cervical intraepithelial neoplasia [CIN]). Cellular immunity may be critical in the elimination of HPV-harboring cells. Interleukin-10, a T-helper type 2 cytokine, has a suppressive effect on cell-mediated immunity. Resistance to apoptosis through the Fas pathway might enable many cancers to escape the immune system. We examined in a large study population whether three polymorphisms in the IL-10 gene and a polymorphism at position -670 of the Fas promotor affect susceptibility for cervical cancer or its precursor. In addition, it was studied whether these polymorphisms were causal and not merely associated by typing microsatellite markers in the region surrounding both genes. A total of 311 CIN, 695 cervical cancer patients, and 115 family-based and 586 unrelated controls were analyzed. Association analysis revealed an increased CIN (II-III) (OR 1.44 [1.06-1.97]) and squamous cell carcinoma of the cervix (OR 1.35 [1.04-1.75]) for individuals heterozygous for the A-allele of the IL-10-592 polymorphism. In contrast to previous findings, no association was found for the IL-10-1082 polymorphism. While an increased risk for adenocarcinoma (AC) in heterozygotes (OR 1.59 [1.02-2.48]) was observed. Our study shows a possible role for the IL-10 gene in CIN and squamous cell cervical cancer susceptibility in the Caucasian population; simultaneously, there might be a role for the Fas gene in the development of AC of the cervix. Further investigations with a higher density of markers are necessary to find the causal mutation.