An increased risk of cervical intra-epithelial neoplasia grade II-III among human papillomavirus positive patients with theHLA-DQA1*0102-DQB1*0602 haplotype: A population-based case–control study of Norwegian women

Human leukocyte antigens (HLAs) present foreign antigens to the immune system and may be important determinants of cervical neoplasia. Previously published associations between HLA and cervical neoplasia exhibit considerable variation in findings. The biomarkers of cervical cancer risk (BCCR) case-control study addressed the role of specific HLA alleles as cofactors in the development of high-grade cervical intraepithelial neoplasia (HG-CIN) based on the most consistent evidence from published literature. Cases (N 5 381) were women with histologically-confirmed HG-CIN attending colposcopy clinics and controls (N 5 884) were women from outpatient clinics with normal cytological screening smears. Subjects were mainly of French-Canadian descent. Cervical specimens were tested for human papillomavirus (HPV) DNA and HLA genotypes by PGMY L1 consensus primer PCR and a PCR sequence-specific primer method, respectively. Unlike other studies, the DQB1*03 and DRB1*13 allele groups were not associated with risk of HG-CIN. The B7-DRB1*1501-DQB1*0602 haplotype was associated with a 41% overall reduction in HG-CIN risk (odds ratio [OR] 5 0.59; 95% confidence interval [CI]: 0.36-0.96), and an 83% reduction in risk of HG-CIN among HPV 16 or HPV 18-positive subjects (OR 5 0.17; 95%CI: 0.05-0.54). Paradoxically, however, the same haplotype was associated with HPV 16/18 infection risk among controls (OR 5 8.44, 95%CI: 1.12-63.73). In conclusion, the B7-DRB1*1501-DQB1*0602 haplotype was protective against HG-CIN, especially in individuals infected with oncogenic HPV, but the mechanism of the association seems to involve multiple steps in the natural history of HPV and CIN. ' 2008 Wiley-Liss, Inc.Key words: cervical intraepithelial neoplasia; human leukocyte antigen; human papillomavirus; case-control study After breast cancer, cervical cancer is the second most common cancer in women worldwide, with 493,000 new cases and over 273,000 deaths annually. 1 It is well established that the cervical infection caused by one of up to 18 oncogenic human papillomaviruses (HPV) is the main causal factor in cervical cancer, with HPV 16 alone accounting for over half of all cases. 2 In fact, HPV infection can be considered a necessary intermediate step in cervical carcinogenesis. 3 On the other hand, despite the presence of asymptomatic cervical HPV infection in 5-50% of women of reproductive age, 4,5 only a small fraction of infected women will develop cervical cancer. Thus, HPV infection alone is not a sufficient cause of cervical cancer, which underscores the need to identify cofactors that may mediate risk of persistent HPV infection or progression to cervical dysplastic changes and overt neoplasia. The human leukocyte antigens (HLA) mediate the presentation of HPV antigens to the immune system and thus may either predispose to or protect against development of HPV-associated cervical neoplasia. 6 Previous case-control studies examining the relationship have suggested that certain HLA polymorphisms are associated with risk of neoplastic tran...

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Selected class I and class II HLA alleles and haplotypes and risk of high‐grade cervical intraepithelial neoplasia

Ades

Koushik

Duarte-Franco

et al. 2008

“…16,17 The aim of our study was to test the hypothesis that HLADR15-DQ6 association demonstrated in our earlier CIN study is also true for the invasive cervical cancer study. We performed a populationbased cohort study of the risk of invasive cervical cancer in relation to these HLA haplotypes and to HPV infection.…”

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confidence: 93%

Risk of invasive cervical cancer associated with polymorphic HLA DR/DQ haplotypes

Ghaderi¹,

Wallin²,

Wiklund³

et al. 2002

The genes encoding human leukocyte antigens (HLA) have shown to be associated with cervical neoplasia. To obtain reliable data on HLA associations with cervical tumors, the study should be performed within a strictly defined cohort. To investigate the population attributable risk of cervical cancer associated with the HLA class II haplotypes DR15 and DQ6 (DQA1*0102 and DQB1*0602), we performed a nested case-control study of 85 women who developed invasive cervical cancer and 120 healthy women from a population-based cohort of Swedish women. The relative risks of cervical cancer among DR15 and DQ6-positive women were 3.73 [confidence interval (CI): 1. Susceptibility to viral infections is partly controlled by the human leukocyte antigens (HLA). Certain HLA specificities are associated with efficient virus elimination while others are associated with a tendency towards long lasting, persistent virus infections. [1][2][3][4][5] Infection with oncogenic human papillomaviruses (HPV), particularly type 16 and 18, is the major cause of cervical intraepithelial neoplasia (CIN) and cervical cancer 6 -8 Although over 90% of cervical cancers harbor HPV genomes, 9 only a small fraction of women infected with high-risk papillomaviruses develop cancer, suggesting that other environmental and/or genetic factors contribute to cervical carcinogenesis. Both studies of monozygotic and dizygotic twins 10 and family studies 11 have found evidence of a genetic component in cervical cancer. Several studies have reported HLA as one genetic factor that is associated with CIN and cervical cancer. 12-14 However, a link between HLA polymorphisms and cervical neoplasia has not been consistently reported. 15 Varying results could be due to the fact that many studies did not use epidemiologically defined study designs. For valid results, acceptable response rates are required.Two previous studies, a population-based cohort study and a population-based case-control study with high attendance rate, both identified HLA-DQ6 and HLA-DR15 as a susceptibility marker for high grade CIN in Scandinavia. 16,17 The aim of our study was to test the hypothesis that HLADR15-DQ6 association demonstrated in our earlier CIN study is also true for the invasive cervical cancer study. We performed a populationbased cohort study of the risk of invasive cervical cancer in relation to these HLA haplotypes and to HPV infection. METHODS Study baseIn the Västerbotten County in Northern Sweden [population, 260,472; women, 130,651 (1995)], a population-based invitational cervical screening program started in 1969 with invitations issued at 4-year intervals. The attendance rate was Ͼ80 percent during the follow-up. All cytological diagnoses in this county, both on Papsmears taken in the organized program and on spontaneously taken smears, are made and the smears stored at the Cytology Laboratory, Umeå University Hospital since 1969. Similarly, all histological specimens from the Västerbotten population have been examined and stored at the Pathology laboratory of the same...

“…[13][14][15] The DQB1*0602-DRB1*1501 and DQA1*0102-DQB1*0602 haplotypes have been found to be associated with increasing risk of cervical cancer in the HPV16 infected women. [16][17][18] Protective effects of certain HLA class II alleles have also been reported. A metaanalysis showed the evidence of protective effect of DQB1*0603 and DRB1*13 alleles.…”

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Polymorphic amino acids at codons 9 and 37 of HLA‐DQB1 alleles may confer susceptibility to cervical cancer among Chinese women

Chen

et al. 2006

Cervical cancer is strongly associated with the infection by oncogenic forms of human papillomavirus (HPV). Although most women are able to clear HPV infection, some develop persistent infections that may lead to cancer, implying genetic susceptibility factors for malignant progression. To verify whether HLA class II DQB1 polymorphism is related to cervical cancer in Chinese population, HLA-DQB typing was carried out by PCR-SBT for 258 patients with cervical cancer and 284 healthy controls, and the allele frequencies were calculated. In this study, HLA-DQB1*060101 and DQB1*0602 alleles were significantly higher in the HPV16 infected patients with cervical cancer compared with healthy controls (v 2 5 31.7452, p < 0.0001; v 2 5 12.7838, p c 5 0.0066), but DQB1*050201 allele was significantly lower (v 2 5 26.2187, p < 0.0001). This result indicates that HLA-DQB1*060101 and DQB1*0602 may confer susceptibility to cervical cancer, and DQB1*050201 may contribute to the resistance to the development of cervical cancer among Chinese women. Sequence analysis reveals that DQB1*060101 allele encodes Leu at position 9 and Asp at position 37, unique to the susceptibility to cervical cancer, whereas the other DQB1 alleles encode Phe or Tyr and Ile or Tyr at the same two positions, respectively. This finding implies that polymorphic amino acids at the putative antigen binding residues 9 and 37 of HLA-DQB1 alleles may play an important role in the development of cervical cancer. ' 2006 Wiley-Liss, Inc.Key words: cervical cancer; HLA; polymorphism; human papillomavirus; susceptibility Cervical cancer is the second most common cancer in women, accounting for 9.8% of all new cancer cases worldwide (371,200 new cases per year), with a disproportionate share of the mortality associated with this disease occurring in developing countries. 1 Human papillomavirus (HPV) is the major etiologic factor in cervical cancer and is found in the majority of cervical tumors. 2 Infections are common but only a small fraction progresses into persistent infection and cancer, suggesting that other factors are needed for the pathogenesis. 3 One potential cofactor may be the host cellular immune response to HPV infection, mediated by HLA-restricted T lymphocytes. To date, there are more than 100 different HPV genotypes. There are 40 known genital HPVs, which are further divided into high-risk (oncogenic: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82, et al.) and low risk (e.g. 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, et al.) types. 4,5 HPV 16 is the most common type associated with cervical cancer worldwide, with little geographic variation. 6 Naturally occurring HPV-16 variants differ in certain biologic properties and might result in differences in pathogenicity. However, previous studies showed that HPV16 E6 variants appeared to be correlated with distinct MHC class II haplotypes. 7,8 Engelmark et al. 9 reported that the HLA class II genes represented a major genetic susceptibility region to cervical cancer in contrary to the clas...