Tumor necrosis factor A and MHC class I chain related gene A (MIC-A) polymorphisms in Swedish patients with cervical cancer
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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HLA class I chain-related MICA and MICB genes polymorphism in healthy individuals from the Bulgarian population
2022, Human ImmunologyCitation Excerpt :Thus, MIC-NKG2D interaction is a very efficient mechanism for activating the cytotoxic immune response and protecting the organism against malignancies, infectious and autoimmune diseases [12]. Due to the important role of MICA and MICB for the development of protective immune response and their close location to the HLA-B locus, there has been growing interest in the investigation of MIC gene polymorphism and their role to the development of different diseases [13–19]. Furthermore, several studies have demonstrated the impact of MICA in organ [20–24] and hematopoietic stem cell transplantations [25–28].
Targeting TNF: A therapeutic strategy for Alzheimer's disease
2014, Drug Discovery TodayCitation Excerpt :The human TNFα cDNA and gene have been cloned [1,2]. The gene is located on chromosome 6 between 6p21.1 and 6p21.3, which is within the human leukocyte antigen (HLA) class III region [3–7]. This suggests that TNFα is an important mediator of inflammatory responses with multiple biological activities.
Association of MICA and MICB alleles with symptomatic dengue infection
2011, Human ImmunologyCitation Excerpt :Previous reports from Cuba support the involvement of the HLA [4], FcγRIIa-R/R131 genotype, and a polymorphic form of tumor necrosis factor-α [15] in the development of dengue disease [16]. Taking into account these observations, the biologic function, and the relevance of MIC genes for infectious diseases [7–9,17], we studied the possible association of some allelic variants of MICA and MICB genes in the pathogenesis of dengue in Cuba. We describe for the first time the predominant allelic forms MICA*008 and MICB*005 in the Cuban population.
MICA polymorphism: biology and importance in immunity and disease
2010, Trends in Molecular MedicineCitation Excerpt :Cervical cancer was among the first malignant diseases investigated. Although no significant association was found between MICA alleles and cervical cancer [70–73], a number of MICA polymorphisms have been reported as risk factors for other cancer types. For example, MICA*A9 in the Chinese Han population [74] and SNP MICA-129val in a Tunisian population [75] are associated with nasopharyngeal carcinoma.
Association between human leukocyte antigen class II alleles and human papillomavirus-mediated cervical cancer in Indian women
2009, Human ImmunologyCitation Excerpt :Individually, DQB1*0602 was not associated with cervical cancer cases; however, contrary reports are available from Tanzanian [41] populations and Honduran [42] and Swedish cervical cancer cases [27] with HR-HPV infection, as well as Iranian [43], Japanese [44], African American [40], and Vietnamese populations [45]. In addition, DQB1*06 in haplotypic association with TNF-11 (DQB1*06-TNF-11 haplotype) was also significantly associated with cervical cancer cases in a Swedish population [46]. Interestingly, among cervical cases, the DRB1*04 allele was positively associated (pc = 0.012) with precancerous cases, with a relative risk of about 3.6-fold in comparison to controls.
MHC Class I Chain-Related Gene A Diversity in Head and Neck Squamous Cell Carcinoma
2006, Human Immunology
- 1
New address (K.-L.W.): Cancer Centre Karolinska, CCK, R8:04, Karolinska Hospital, S-171 76 Stockholm, Sweden.
- 2
New address (J.D.): Department of Medical Microbiology, MAS University Hospital, Lund University, Malmö, Sweden.