Interleukin-10 and Fas polymorphisms and susceptibility for (pre)neoplastic cervical disease

Abstract

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.

Variants of chemokine receptor 2 and interleukin 4 receptor, but not interleukin 10 or Fas ligand, increase risk of cervical cancer

“…There was no association for the SNP at position 21082 and no difference in the distribution of haplotypes between cases and controls. 22 In their dataset, the polymorphism at position 2819 showed strong linkage disequilibrium (LD) with position 2592, in agreement with several previous reports claiming that these SNPs make up the three major haplotypes GCC, ACC and ATA (21082, 2819, 2592). [22][23][24]50 An earlier study on 77 patients with cancer and 69 controls reported an increased risk of cervical cancer for subjects carrying the 21082 G allele in the Shona ethnic group of Zimbabwe.…”

“…22 In their dataset, the polymorphism at position 2819 showed strong linkage disequilibrium (LD) with position 2592, in agreement with several previous reports claiming that these SNPs make up the three major haplotypes GCC, ACC and ATA (21082, 2819, 2592). [22][23][24]50 An earlier study on 77 patients with cancer and 69 controls reported an increased risk of cervical cancer for subjects carrying the 21082 G allele in the Shona ethnic group of Zimbabwe. 21 A third study investigated the 3 promoter polymorphisms using 144 Korean patients with invasive cervical cancer and 179 controls and does not detect any association; the 21082 position is not polymorphic in the Korean population.…”

“…Zoodsma et al report a frequency of the 2592 A-allele of 23% in cases (both CIN and carcinomas) and 19% in controls, 22 whereas in our data the A-allele occurred at 24% in both cases and controls. Hence, the effect that could be detected in both CIN and cervical cancer patients in Caucasian population from the Netherlands was not seen in our sample of mainly cancer in situ cases of Swedish origin.…”

“…23,24 A recent Dutch study including 1,006 patients (311 CIN 1 695 cervical cancer patients) and 643 controls investigated the influence of these polymorphisms on risk of cervical cancer in the Caucasian population and revealed an association with the 2592 A-allele and risk of cervical cancer. 22 The present study aimed to examine the importance of this polymorphism in our Swedish cervical cancer cohort.…”

“…19 Several groups have proposed IL-10 as a candidate gene for cervical cancer. [20][21][22] Polymorphisms at positions 2592, 2819 and 21082 in the promoter region of IL-10 define three haplotypes and have been suggested to influence IL-10 production. 23,24 A recent Dutch study including 1,006 patients (311 CIN 1 695 cervical cancer patients) and 643 controls investigated the influence of these polymorphisms on risk of cervical cancer in the Caucasian population and revealed an association with the 2592 A-allele and risk of cervical cancer.…”