The Health Outcome
Approximately 400,000 incident cases of cervical cancer occur annually worldwide, making it the second or third leading cause of cancer in women. Research studies have identified several risk factors for developing cervical cancer, including HPV infection. Although human papillomavirus (HPV) infection is common, only a small percentage of women infected with HPV will develop persistent infection; an even smaller percentage of those with persistent infection will develop cervical intraepithelial neoplasia (CIN), and fewer yet will develop cervical cancer, thus suggesting that immunological and genetic co-factors are involved in cervical carcinogenesis.
The Finding
The investigators conducted a case-control study to determine the relationship between MHC class I chain-related gene A (MICA) and tumor necrosis factor A (TNFA) polymorphisms with cervical cancer. The study was conducted out of a population-based cohort study of Swedish women and consisted of 85 case subjects with cervical cancer and 120 healthy control subjects. Gene polymorphisms within HLA DR-DQ, MICA, and TNFA were assessed, and HPV DNA positivity were measured. Neither MICA or TNFA polymorphisms were independently associated with cervical cancer (1). A detailed abstraction of this article is available online as part of the HuGENet™ e-Journal club (2). Women eligible for the study were defined as Vasterbotten residents with at least one cytologically normal cervical smear between 1969 and 1995. Cases were derived from the Swedish Cancer Registry (includes results of histologic diagnosis), which was linked to a cytology database. Control subjects were defined as women in the study base who did not develop cervical cancer before the time of diagnosis of a corresponding case and matched to case subjects for age and time of sampling. Women (case and control subjects) who had prior operative treatment of the cervix were excluded from the study. Genotyping for MICA alleles 4, 5, 5.1, 6, and 9 were reported, as were TNFA alleles a2, a4, a5, a6, a10 and a11. HPV DNA positivity was detected via consensus primers MY09 and MY11 and GP5+ and GP6+. Genomic and HPV DNA was extracted from archival smears and biopsies. Although the authors did not find significant independent associations between TNF and MICA alleles, they do report the findings for TNFa-11 (Odds Ratio: 1.17) and indicate its association with DQ6 as part of the HLA DQ6-TNFa-11 extended haplotype. The authors conclude as their main finding that the HLA DQ6-TNFa-11 extended haplotype increases the risk for cervical cancer three times (OR: 3.08, Confidence Interval=1.30, 7.31), and serves to further support prior findings that HLA DQ6-DR15 is associated with increased risk for cervical cancer. The authors conclude that on the basis of the total HLA typing done for a larger group of women from the same cohort, the HLA class II DQ6-DR15 haplotype was the most attributable HLA locus for development of cervical cancer.
Public Health Implications
The results presented are suggestive. Although the HLA class II DQ6-DR15 haplotype association has been reported in the literature, this association is not unanimously supported. The authors' main hypothesis did not reveal associations between TNFA and MICA with cervical cancer, but their results were used to indirectly support this prior hypothesis. It is unclear how this study's findings will impact public health. The logical next step is to understand the epitope for the HLA haplotype and to determine at which step the haplotype plays a role (e.g., HPV infection, persistence, cancer progression). Further laboratory and epidemiological studies are needed, particularly to assess the implications of multiple factors, since a relatively rare HLA haplotype is likely only one of a multitude of factors playing a role in cervical cancer development.
References
- Ghaderi M, Zake LN, Wallin KL, Wiklund F, Hallmans G, Lenner P, Dillner J, Sanjeevi C. Tumor necrosis factor A and MHC class I chain related gene A (MIC-A) polymorphisms in Swedish patients with cervical cancer. Human Immunology 2001;62:1153-58.
- Ghaderi M et al. e-Journal Club abstraction form
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