Elsevier

Human Immunology

Volume 62, Issue 10, October 2001, Pages 1153-1158
Human Immunology

Tumor necrosis factor A and MHC class I chain related gene A (MIC-A) polymorphisms in Swedish patients with cervical cancer

https://doi.org/10.1016/S0198-8859(01)00306-8Get rights and content

Abstract

Human papillomaviruses type 16 and 18 are the major cause of cervical cancer. However, genetic factors contribute to the propensity of persistent HPV infection and cervical carcinoma. Allelic variants of the human leukocyte genes have shown to be associated with cervical neoplasia. The strongest associations have been found with the genes in the HLA class II region. The aim of this study was to analyze the association of two non-HLA class II markers with invasive cervical cancer. Microsatellite polymorphism of the TNFA gene located in the class III region and a short tandem repeat polymorphism of the MICA gene located in the centromeric end of the HLA class I region were analyzed. Eighty-five patients and 120 matched control individuals from a population-based cohort from Northern Sweden participated in this nested case-control study. MICA was not associated with cervical carcinoma. TNFa-11 frequency was increased in the HPV18 DNA positive patients (OR = 2.84, p = 0.0481, CI = 1.04–7.78, pc = NS). TNFa-11 was not associated with susceptibility to HPV16 infection, but it increased the risk for cervical cancer with the HLA DQ6 (DQA 1∗0102–DQB 1∗0602) haplotype. Our findings indicate that the association of TNFA with cervical cancer is different with CIN. The extended HLA DQ6-TNFa-11 haplotype is increasing the risk for development of cervical cancer significantly (OR = 3.08, p = 0.0104, CI = 1.30–7.31).

Introduction

The major cause of cervical cancer is considered to be infection with high-risk types of human papillomaviruses (HPV) 16 and 18 1, 2, 3. Although many women are infected with oncogenic HPV’s, they usually do not develop cervical tumors. The transient HPV infections and regression of cervical intraepithelial neoplasia (CIN) lesions to normal epithelia, suggest that immunological and genetic co-factors are involved in the cervical carcinogenesis. Occurrence of HPV associated CIN in immunosuppressed patients is supporting the hypothesis that immune responses against persistent HPV infections are playing a key role in transformation of epithelial cells 4, 5.

Magnusson et al. compared the incidence of cervical cancer in relatives of cases of cervical cancer and controls, and found a significant familial clustering among biologic, but not adoptive, relatives [6]. The Swedish State registry was used to sort relatives of cases with cervical cancer and randomly selected age-matched controls. A study of monozygotic and dizygotic twins has also shown an inherited link to different cancer types [7].

Candidate gene studies have implicated several immunogenetic polymorphisms in human infectious and cancer diseases. Among them HLA variation has been of interest since genes located in the HLA region have shown to be associated with viral infections 8, 9. Numerous association studies have been done of genetic polymorphisms closer to the tumor necrosis factor gene located in the class III region of the human MHC 10, 11. The associations of TNFA gene with infectious diseases has been independent of the HLA class I and class II variations. The polymorphic human major histocompatibility genes have revealed several associations with cervical cancer and CIN 12, 13, 14.

Most of these findings point out the association genes at the HLA class II loci, whereas other genetic markers on the human MHC have not been adequately studied. We reported earlier correlations of a microsatellite polymorphism in the TNF loci and a short tandem repeat (STR) of the MHC class I chain related gene MICA with cervical neoplasia 13, 16. TNFa-11 increased the risk of HPV 16 infection. TNFa-11, as an extended haplotype with HLA DQ6-DR15 increased the risk for CIN. The MICA gene located in the centromeric end of HLA class I did not show any significant association with CIN.

The aim was to study two distinct non-HLA class II genes in relation to cervical cancer in a population-based cohort study of Swedish women: (1) to determine if a susceptibility or protective gene is located in the class III or class I of the human MHC; (2) to determine whether MICA or TNFA polymorphisms are associated with invasive cervical cancer; and (3) to see if TNFA or MICA gene associations with cervical cancer are the same as CIN.

Section snippets

Study design

In total 85 case women with cervical cancer and 120 healthy controls were analyzed for HLA DR-DQ, MICA, and TNFA gene polymorphisms in addition to HPV.

Eligible women for the study were defined as Västerbotten resident who had had at least one cytologically normal cervical smear and who had no prior operative treatment of the cervix. Linkage between the cytology registry and the Swedish Cancer Registry from 1969 to 1995 identified 133 eligible women with invasive cervical cancer diagnosed after

Results

Frequency of the most common alleles of TNFA and MICA gene is shown in Table 1. We subdivided the patient group into HPV 16 and HPV 18 positives and negatives to see if any of the analyzed alleles are related to HPV infection. None of the alleles were directly associated with cervical cancer.

TNFa-11 frequency was higher among HPV 18 DNA positive patients compared to HPV 18 DNA negative patients (OR = 2.84, CI = 1.0391–7.7828, p = 0.0481). This association was not significant after the

Discussion

The main environmental risk determinant for development of cervical carcinoma is persistent infection of oncogenic HPV types [2]. Persistence of HPV infection might be influenced through repetitive exposure to the viral DNA by for instance the number of sexual partners [28] and inherited genes [29]. Other host factors such as cytokine production and hormone levels do also play a role in the rate of tumor development 30, 31.

Candidate gene studies have identified several associations in the HLA

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    2

    New address (J.D.): Department of Medical Microbiology, MAS University Hospital, Lund University, Malmö, Sweden.

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