Lack of association of HLA polymorphisms with human papillomavirus-related cervical cancer

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...

Section: Discussionsupporting

confidence: 62%

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

“…7,11,[26][27][28][29] Also, in an affected sib-pair study, we have found further evidence that the class II region rather than the region containing the HLA class I loci is linked to cervical carcinoma in situ. 30 A high viral load of HPV 16 several years before diagnosis markedly increases the risk of CIS development.…”

Section: Discussionsupporting

confidence: 51%

“…[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.…”

mentioning

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 ...

“…[12][13][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.…”

mentioning

confidence: 99%

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...