HLA DR–DQ associations with cervical carcinoma show papillomavirus–type specificity

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...

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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

“…20 Thirteen high-risk HPV genotypes included in the probe B cocktail were found to be of HPV genotypes 16,18,31,33,35,39,45, 51, 52, 56, 58, 59, 68.…”

Section: Study Procedures and Collection Of Specimensmentioning

confidence: 99%

“…[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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confidence: 99%

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...

“…[4][5][6] Certain HLA class II alleles, such as DRB1*1501 and DQB1*0602, have been shown to increase the risk for cervical carcinoma, most strongly in HPV 16-positive carcinomas. [7][8][9][10][11][12][13] We have previously shown that the increased carcinoma risk primarily depends on that the alleles render carriers more susceptible to HPV16 infections. 12 In addition, carriers of these HLA susceptibility alleles had higher HPV 16 load in their cervical smears compared to HPV 16-positive noncarriers.…”

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confidence: 99%

HLA class II allele control of HPV load in carcinoma in situ of the cervix uteri

Beskow

Moberg

Gyllensten

2005

Human papillomavirus (HPV) infection is the most important risk factor for development of cervical carcinoma. Carriers of certain HLA class II alleles, e.g., DRB1*1501 and DQB1*0602, are more prone to HPV 16 infection and cervical carcinoma, whereas other alleles, e.g., DRB1*1301 and DQB1*0603, render carriers less susceptible to the disease. In our study comprising 484 cases and 601 controls, we examine the effect of HLA class II alleles on viral load of the oncogenic types HPV 18/45 and HPV 31 and risk of developing cervical carcinoma in situ. We find that carriers of the commonly reported protective DRB1*1301 and DQB1*0603 alleles have lower HPV 18/45 load compared to noncarriers and a lower risk of developing HPV 18/45-positive cervical carcinoma. This provides further evidence that the HLA class II-mediated immune response to HPV is important for controlling viral load and outcome of an infection. ' 2005 Wiley-Liss, Inc.Key words: HLA; human papillomavirus; viral load; cervical carcinoma HPV is the major etiologic risk factor for cervical carcinoma and is found in the majority of cervical tumors. Although infection with oncogenic forms of HPV are common among young women, less than 1% of those infected develop cervical carcinoma. [1][2][3] Both the length of the infection and a high viral load several years before diagnosis have been shown to increase the risk of developing cervical dysplasia and carcinoma in situ (CIS). [4][5][6] Certain HLA class II alleles, such as DRB1*1501 and DQB1*0602, have been shown to increase the risk for cervical carcinoma, most strongly in HPV 16-positive carcinomas. [7][8][9][10][11][12][13] We have previously shown that the increased carcinoma risk primarily depends on that the alleles render carriers more susceptible to HPV16 infections. 12 In addition, carriers of these HLA susceptibility alleles had higher HPV 16 load in their cervical smears compared to HPV 16-positive noncarriers. A plausible hypothesis is that HLA is involved in the cellular immunity against HPV. Also, HLA alleles making carriers more susceptible to HPV infections are likely to be less efficient in triggering immunity and inducing viral clearance. As a consequence, carriers of susceptibility alleles harbor higher HPV load than carriers of more efficient alleles. The relation between viral load and carcinoma development has been most extensively studied for HPV 16, presumably because it is the most prevalent HPV type in cervical tumors throughout most of the world. 1 We have previously examined the effect of HPV 18/45 and HPV 31 viral load on the risk for cervical CIS. 14 Our results showed that higher viral load of HPV 18/45 or HPV 31 increases the risk of CIS, although the risk magnitude is less than that observed for HPV 16. Therefore, it is possible that HLA alleles could influence carcinoma development by affecting viral load also for other HPV types besides HPV 16.A meta analysis demonstrated a protective effect of the DRB1*1301 and DQB1*0603 alleles against development of cervical carcinoma in 18 ...