HPV16感染与新疆哈萨克族食管癌发病及临床病理学研究

背景与目的:人乳头状瘤病毒(human papilloma virus,HPV)作为食管癌发生重要的环境因素备受许多学者的关注,但其相关性未得到一致性公认,尤其对于高发的新疆哈萨克族食管癌.本研究探讨HPV16感染与新疆哈萨克族食管痛发生、发展的相关性.方法:采用半巢式聚合酶链反应(polymerase chain reaction,PCR)技术检测100例新疆哈萨克族食管癌患者癌组织和100例新疆哈萨克族正常人食管正常黏膜组织HPV16 E6的感染情况.结果:新疆哈萨克族食管癌患者HPV16 E6感染率为46%,明显高于新疆哈萨克族正常人群感染率的22%(P<0.001,OR=3.020);HPV16 E6感染与新疆哈萨克族食管癌患者的发病年龄、性别、肿瘤生长部位、淋巴转移、分化程度无明显相关性(P均>0.05).结论:HPV16 E6感染与新疆哈萨克族食管癌发病密切相关,是其发病的重要因素之一.     

新疆哈萨克族食管鳞癌中人乳头状瘤病毒感染的检测

目的：检测新疆哈萨克族食管鳞癌患者中人乳头状瘤病毒（HPV）DNA的总感染率，通过统计学分析，探讨HPV感染与新疆哈萨克族食管鳞癌的相关性。方法：采用聚合酶链反应（PCR）技术检测了318例新疆哈萨克族食管鳞癌（ESCC）石蜡包埋组织中HPV DNA的感染情况，其中117倒用直接裂解法制备样本DNA，201例用酚－氯仿－异戊醇提取DNA；PCR产物双向测序。测序结果应用BLAST在线分析，统计处理采用X^2检验，分析HPV与新疆哈萨克族食管鳞癌发生的相关性。结果：在新疆哈萨克族食管鳞癌组织中，HPV DNA总检出率为64．5％（205／318）。其中直接裂解法组HPV DNA栓出率为82．9％（97／117），酚－氯仿－异戊醇提取DNA纽HPV DNA捡出率为53．7％（108／201），二者之间差异有统计学意义（P〈0．05）。按照病理分化程度对哈萨克族ESCC样本DNA中HPV总感染率进行分析发现，高分化ESCC中HPV阳性率为63.2％，中分化ESCC中HPV阳性率为69．8％，低分化ESCC中HPV阳性率为50．0％，三者之间差异无统计学意（P〉0．05）结论：HPV DNA感染与新疆哈萨克族食管鳞癌存在相关性．可能是新疆哈萨克族食管癌发生的重要因素之一。     

人乳头状瘤病毒感染及人白细胞抗原-DQB1等位基因多态性与南疆维吾尔族女性宫颈癌的关系

目的 探讨人类乳头状瘤病毒(HPV)感染及人类白细胞抗原(HLA)-DQB1等位基因多态性与南疆维吾尔族女性官颈癌的关系.方法 采用导流杂交基因芯片技术,检测190例南疆维吾尔族女性宫颈癌组织和190例正常维吾尔族女性宫颈组织21种HPV亚型的感染情况.采用聚合酶链反应序列特异性寡核苷酸探针(PCR-SSO)检测其5个HLA-DQB1等位基因的基因频率.结果 (1)在对照组中,HPV感染17例,感染率为8.9%.190例宫颈癌中,HPV感染133例,感染率为70.0%,高于对照组(P<0.05).其中HPV16的感染率最高,为64.7%,也明显高于对照组(3.7%,P<0.05).其他亚型的感染率均远低于HPV16,依次为HPV18(2.6%)、HPV68(2.1%)、HPV45(1.6%)、HPV58(1.6%)、HPV39(1.6%)、HPV31(1.1%)、HPV56(1.1%)及HPV59(0.5%),中国汉族人常见类型HPV53和低危型HPV6的感染率均为0.5%.(2)宫颈癌组和对照组的HLA-DQBI*03基因分布差异有统计学意义(P=0.014),携带HLA-DQB1*03基因者罹患宫颈癌的风险降低31.7%(OR=0.683),其他等位基因与维吾尔族女性宫颈癌的发生无关.(3)携带HLA-DQB1*06基因的宫颈癌患者HPV和HPV16的感染率高于非HLA-DQB1*06携带者(P值分别为0.046和0.025),携带HLA-DQB1*06等位基因的维吾尔族女性更容易被HPV和HPV16感染(OR分别为1.808和1.879).其他等位基因与HPV及HPV16感染无关.结论 南疆维吾尔族女性宫颈癌患者的HPV感染率高于非宫颈癌女性,均以HPV16感染为主.HLA-DQB1*03可能为南疆维吾尔族女性罹患宫颈癌的保护基因.HLA-DQB1*06为HPV和HPV16感染的易感基因.     

致癌物代谢酶基因（CYP2C19、GSTT_1）多态性与哈萨克族人群食管癌发病风险关系的研究

目的探讨、相代谢酶基因多态性与新疆哈萨克族人群食管癌发病风险的关系。方法收集经组织病理学确诊的哈萨克族食管鳞癌新发病例88例外周血液标本,提取DNA后用PCR-RFLP技术检测CYP2C19、GSTT1基因多态性。结果食管癌组和对照组中CYP2C19m1、CYP2C19m2基因各型之间差异无统计学意义（P〉0.05）,但食管癌组S-美芬妥英慢代谢者（PM）的患病率为26.1%,为正常对照组11.1%约2倍多,两者差异有统计学意义（χ2=5.72,P〈0.05,相对危险度OR=2.831,95%可信度CI：1.180～6.793）。GSTT1基因缺失型（-）和正常型（＋）频率在对照组中分别为45.4%和54.2%,在哈萨克族食管癌组中分别为64.8%和35.2%,两组间的频率分布差异有统计学意义（P〈0.05,OR=2.173,95%CI：1.149～4.110）。结论相代谢酶基因CYP2C19在哈萨克族人群中具有遗传多态性,CYP2C19m1和CYP2C19m2是两个相互独立的突变型等位基因,CYP2C19慢代谢者参与了食管癌致癌物的灭活,其活性降低时可增加患食管癌的易感性。相代谢酶基因GSTT1基因缺失型（-）可能是哈萨克族人群患食管癌重要的生物标志。对哈萨克族人群进行、相代谢酶基因分型,有助于筛选食管癌发生的高危人群,可为食管癌的预防和早期诊断提供科学依据。     

新疆哈萨克族食管鳞癌中p16蛋白的表达及其意义

目的研究p16蛋白表达与新疆哈萨克族食管鳞癌生物学行为的关系。方法应用免疫组织化学SP法检测30例食管鳞癌和60例正常食管组织中p16蛋白的表达。结果60例正常组织中p16蛋白阳性表达率为88.33%(53/60);30例食管鳞癌组织中p16蛋白表达阳性率为46.67%（14/30）。随着恶性程度增加及病程进展,p16蛋白阳性率逐渐下降,p16在高分化鳞癌组阳性表达率(75%)显著高于低分化鳞癌组(25%)(P<0.05)。结论p16蛋白表达缺失可能与哈萨克族食管癌的发生发展有关。     

新疆哈萨克族食管癌组织中HPV16 E6、E7基因的检测与p53的关系

目的探讨人乳头状瘤病毒(HPV)16型感染在新疆哈萨克族(哈族)食管癌发病中的作用,并分析HPV16感染与p53过表达之间的关系.方法采用聚合酶链(PCR)技术,检测41例食管鳞状细胞癌组织中HPV16 E6与E7基因表达差异;用LSAB免疫组织化学方法分析p53蛋白的表达.结果癌组织中HPV16 E6与E7基因阳性检出率分别为34.15%(14/41)和63.41%(26/41);用免疫组化检出p53蛋白阳性率分别在HPV16 E6阳性组(57.1%)与HPV16 E6阴性组(14.8%)间、HPV16 E7阳性组(42.3%)与HPV16 E7阴性组(6.7%)间均存在显著性差异(P＜0.05);用PCR检出HPV16 E6、E7基因在食管癌的高分化组、中低分化组中的检出率分别为7.69%(1/13)、46.43%(13/28)和38.46%(5/13)、75.00%(21/28),差别均有统计学意义(P＜0.05).结论提示p53基因突变与HPV16感染在哈族食管癌的发病过程中存在相互促进作用;另外,HPV16 E6与E7基因和哈萨克族食管癌病理组织学分级的生物学行为密切相关.     

食管鳞癌中人乳头瘤病毒16型E6、E7和细胞特异性增强子片段的检测

目的:检测食管鳞癌组织中人乳头瘤病毒(HPV)16 E6、E7基因和细胞特异性增强子片段(CTSE).方法:采用聚合酶链反应法(PCR)检测40例食管鳞癌和20例正常食管黏膜中HPV16 E6、E7基因和病毒长控制区内(long control region,LCR)的细胞型特异性增强子(cell type specific enhancer,CTSE).结果:在40例食管鳞癌中,HPV16 的E6、E7基因和CTSE片段的检出率分别是37.5%(15/40)、42.5%(17/40)和40%(16/40),20例正常食管黏膜中E6、E7和CTSE的检出率分别为0%(0/20)、0%(0/20)和5%(1/20),两者均存在显著性差异(P<0.05).CTSE片段分别与E6和E7 基因有明显相关性(P<0.05).食管鳞癌中E6 、E7基因及CTSE的检出率在患者不同性别、年龄、肿瘤浸润程度、淋巴结转移和组织学分级肿瘤中差异均无显著性(P>0.05). 结论:E6和E7基因与CTSE 片段共存于HPV16感染的食管鳞癌组织中,三者可能与食管鳞癌的发生和发展有关.     

CYPlA1、GSTMl基因多态性及环境因素与新疆哈萨克族食管癌家族聚集性的相关性研究

目的探讨CYPlAl、GSTMI基因多态性及环境因素与新疆哈萨克族食管癌家族聚集性发生的关系。方法通过检测86例新疆哈萨克族食管癌家族及82例对照家族外周血CYPlAl、GSTMl基因的多态性,并通过对环境危险因素进行现场问卷调查,探讨CYPlAl、GSTMI基因和环境因素在新疆哈萨克族食管癌家族聚集性中所起的作用。结果在新疆哈萨克族食管癌家族与对照家族之间cⅥ,1A1MspI、GSTMl不同基因型的分布频率差异均有统计学意义（P〈0．05）,MspI突变型和GSTMl缺失型之间交互作用显著增加食管癌家族集聚性,OR值为3．193（95％CI：1．645—3．376）,Logistic多因素分析显示新疆哈萨克族食管癌家族聚集性的发生与饮水情况、摄人较多新鲜蔬菜水果、CYPlAl基因MspI多态性等3个因素具有相关性,其中摄入较多新鲜蔬菜水果（OR=0。278,95％CI：0．137—0．551）是新疆哈萨克族食管癌家族聚集性的保护因素,饮用河水（OR=3．468,95％CI：1．562—6．551）、CYPlAI基因Mspl多态性的突变表型（OR=2．732,95％CI：1．741—3．886）是新疆哈萨克族食管癌家族聚集性的危险因素。结论CYPlAl、GSTMl基因多态性在新疆哈萨克族食管癌家族聚集性中起了一定的作用,饮用河水、CYPlAl基因Mspl突变表型是新疆哈萨克族食管癌家族聚集性的危险因素,可能与这些家族成员食管癌高发有关。     

新疆哈萨克族食管鳞癌组织Smad4基因启动子甲基化的检测

目的：检测新疆哈萨克族食管鳞癌组织中抑癌基因Smad4启动子区的甲基化状态,并描述其在哈萨克族食管鳞癌发生和发展中的作用。方法：应用MassARRAY技术平台检测2009—01-01—2011—10-31新源县人民医院收集的新疆食管癌高发区-伊犁哈萨克自治州哈萨克族食管鳞癌组织37例和当地正常人食管组织33例中Smad4基因启动子的甲基化状态。结果：哈萨克族食管癌组与对照组中Smad4基因启动子的12个CpG单位,6-甲基化率的平均值分别为40．07％和30．15％,差异有统计学意义,Z=-2．611,P=0．01】。哈萨克族食管鳞癌组织和正常人食管组织中Smad4基因启动子区CpG-1的平均甲基化水平分别为1．7％和O．7％,z=-2．2,P=0．028;CpG-16—19的平均甲基化水平分别为4．5％和2．2％,z=-3．3,P=0．001;CpG-27—28的平均甲基化水平分别为4．9％和3．0％,z=-2．6,P=0．007;CpG-31—33的平均甲基化水平分别为6．8％和5．5％,z=-2．5,P=0．012。结论：Smad4基因启动子甲基化参与了哈萨克族食管癌的发生和发展,Smad4基因启动子区CpG-1、CpG-16—17—18—19、CpG-27—28和CpG-31—32—33甲基化状态的改变可能与新疆哈萨克族食管癌发生和发展有关。     

河南地区食管鳞癌和贲门腺癌与人乳头瘤病毒感染相关性的分析

目的:了解人乳头瘤病毒16型(HPV16)与河南食管癌高发地区食管鳞癌、贲门腺癌发生的关系.方法:利用聚合酶链式反应(PCR)对高发区食管鳞癌组织(44例)、贲门腺癌组织(18例)进行HPV-DNA检测.结果:食管鳞癌及贲门腺癌组织中均检测到HPV16 E6 DNA表达,但食管鳞癌HPV16 E6 DNA表达(84%,37/44)明显高于贲门腺癌(44%,8/18),P<0.01.食管鳞癌及贲门腺癌组织中,高危型HPV16 E6 DNA表达与患者年龄、性别、分化程度、浸润程度,淋巴结转移以及肿瘤分级无相关性,P值均＞0.05.结论:同一地区食管鳞癌和贲门腺癌均有不同程度HPV感染,提示HPV可能是两者共同相关致病危险因素,高危型HPV16感染可能在食管鳞癌和贲门腺癌发生中起重要作用.     

Association between high-risk HPV types, HLA DRB1* and DQB1* alleles and cervical cancer in British women

Cervical scrapes from 116 British women referred with cervical cancer were tested for the presence of high oncogenic risk human papillomavirus (HPV) genotypes (HPV(hr)). Ninety-four per cent of the scrapes had one or more of these virus types and 66% were HPV16-positive. HPV18 was more frequent in adenocarcinoma. No evidence was found for an increased cancer risk associated with the HPV16 E6 350G variant. The HLA DRB1* and DQB1* alleles in these women and in 155 women with normal cytology and negative for HPV(hr) DNA were compared. DQB1*0301 alone (2P = 0.02) and in combination with DRB1*0401 (2P = 0.02) was found to be associated with cervical cancer. This was more marked in cancers positive for HPV types other than HPV16. In contrast, DRB1*1501 alone and in combination with DQB1*0602 was not significantly elevated in cancers overall, but did show some excess in HPV16-positive cancers (2P = 0.05), associated with HPV16-positive cervical cancers. Taking all cancers together, a marginally significant protective effect was found for DQB1*0501 (2P = 0.03) but no protective effect could be seen for DRB1*1301.     

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

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 (chi(2) = 31.7452, p < 0.0001; chi(2) = 12.7838, p(c) = 0.0066), but DQB1*050201 allele was significantly lower (chi(2) = 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.     

HLA class II alleles associated with infection by HPV16 in cervical cancer in situ

HLA class II alleles have been associated with an increased risk of developing cervical cancer through infection with oncogenic forms of human papilloma virus (HPV). We have examined the association of variation at the DRB1 and DQB1 loci with HPV16 infection and risk of development of cervical cancer by analysis of 440 cases diagnosed with cervical cancer in situ and 476 age-matched controls in a retrospective case-control study. The infection history of a woman was studied by analysis of cervical smears taken at multiple times during a period of up to 27 years (1969-95). The frequency of a number of alleles are either increased (DRB1*0801, DRB1*1501, DQB1*0402 and DQB1*0602) or decreased (DRB1*0101, DRB1*1301, DQB1*0501 and DQB1*0603) in the cancer patients compared to the controls. After correction for multiple testing, only the DQB1*0602 and the DRB1*1501 alleles remain associated with cancer and only in HPV16-infected patients (DQB1*0602: 102/264 (39%) vs. 130/476 (28%), p = 0.028 and DRB1*1501: 104/259 (40%) vs. 132/469 (28%), p = 0.027). These alleles are associated primarily with infection by HPV and only indirectly affect the risk of developing cervical cancer in situ. To study the impact of these alleles on persistence of infection, women with short-term infections were compared to those with long-term infections. Carriers of DQB1*0602 and DRB1*1501 were more frequent in the group with long-term HPV infections, indicating that these class II alleles contribute to the inability to clear an HPV infection.     

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

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.     

Host genetic control of HPV 16 titer in carcinoma in situ of the cervix uteri

Cervical cancer is strongly associated with infection by oncogenic forms of human papillomavirus (HPV). Although most women are able to clear an HPV infection, some develop persistent infections that may lead to cancer. The determinants of persistent infection are largely unknown. We have previously shown that women developing carcinoma in situ of the cervix uteri have higher titers of HPV 16 long before development of cervical neoplasia, indicating that the immune response to HPV is important in determining the outcome of an infection. The HLA class II alleles DRB1*1501 and DQB1*0602 have previously been associated with an increased risk of HPV infection, and carriers of these alleles also tend to have more long-term infections. Together these results indicate that certain HLA alleles may affect the ability to control the HPV copy number. To evaluate this possibility, we studied the HLA class II DRB1*1501-DQB1*0602 haplotype, as well as the alleles individually, and the HPV 16 titer in 928 women from a retrospective case-control study (441 cases and 487 controls). Carriers of the haplotype DRB1*1501-DQB1*0602 allele have a significantly higher HPV 16 titer compared to noncarriers (t-test with unequal variance, p = 0.017). An association was found between the HLA haplotype carrier frequency and HPV 16 titer (Mantel-Haenszel statistics p = 0.005). To study whether titer is related to the persistency of infection, women were divided into groups with long-term and short-term infection. A strong correlation is seen between long-term infection and high viral load and between short-term infection and low viral load. These results show that host genetic factors, e.g., variation at the HLA class II loci studied, may affect the immune reaction to the virus and thereby indirectly increase the susceptibility to carcinoma in situ of the cervix uteri.     

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

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 = 381) were women with histologically-confirmed HG-CIN attending colposcopy clinics and controls (N = 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] = 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 = 0.17; 95%CI: 0.05-0.54). Paradoxically, however, the same haplotype was associated with HPV 16/18 infection risk among controls (OR = 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.     

Association of HLA-DQB1*0301 and HLA-DQB1*0602 with different subtypes of gastric cancer in Taiwan.

Gastric cancer (GC) is a heterogeneous disorder with multifactorial etiologies. Genetic predisposition, environmental factors, and Helicobacter pylori infection are thought to interact in the manifestation of GC. Particular human leukocyte antigen (HLA) alleles play a pivotal role in cellular immunity and may be an important genetically determined host trait. To elucidate the association between the genotype of HLA class II genes and the clinical phenotype of GC, polymorphisms of HLA-DRB1 and HLA-DQB1 were determined by polymerase chain reaction with sequence-specific primers in 106 Taiwanese patients with GC and in 208 healthy controls. Comparison of allele frequencies between GC patients and healthy controls showed no significant difference at the HLA-DRB1 locus. Patients with GC had a higher frequency of DQB1(*)0602 (9.4% vs. 3.6%, P < 0.05, odds ratio 2.79, 95% confidence interval 1.41 - 5.47) and a lower frequency of DQB1(*)0301 (14.6% vs. 23.8%, P < 0.05, odds ratio 0.55, 95% confidence interval 0.35 - 0.85) compared to healthy controls. Correlation of HLA-DQB1 status with clinicopathologic features revealed predominance of male gender (16/3 vs. 50/37, P < 0.05) and proximal location (12/7 vs. 28/59, P < 0.05) in patients with positive HLA-DBQ1(*)0602 compared to those with negative HLA-DBQ1(*)0602. In contrast, a higher ratio of diffuse/intestinal subtype (20/10 vs. 30/46, P < 0.05) and a lower seropositivity of Helicobacter pylori (14/30 vs. 58/76, P < 0.005) were noted in patients with positive HLA-DQB1(*)0301 compared to those with negative HLA-DQB1(*)0301. In conclusion, HLA-DQB1(*)0602 confers susceptibility to gastric cancer, especially for male Taiwanese and proximal tumor location, while HLA-DQB1(*)0301 may have a protective effect on GC, probably through resistance to Helicobacter pylori infection. HLA-DQB1 alleles are associated with susceptibility or resistance to GC and also influence its clinical features.     

Association between human leukocyte antigen polymorphism and human papillomavirus 16-positive vulval intraepithelial neoplasia in British women

Polymorphisms in human leukocyte antigen (HLA) genes have been implicated in the risk for developing human papillomavirus (HPV)-associated cervical neoplasia. By comparison with local cadaver controls typed for HLA class I (n = 946) and II (n = 144) antigens, HPV-16-positive high grade vulval intraepithelial neoplasia patients (n = 42) showed significantly different frequencies of HLA-A2 [odds ratio (OR), 2.1; confidence interval (CI), 1.4-3.9], HLA-B7 (OR, 2.6; CI, 1.4-4.7), HLA-DRB1*01(01/02/04) (OR, 0.1; CI, 0.03-0.5), HLA-DRB1*11 (OR, 3.3; CI, 1.4-7.1), HLA-DRB1*13 (OR, 0), HLA-DQB1*05 (OR, 0.2; CI, 0.05-0.6), and HLA-DQB1*03032 (OR, 4.6; CI, 1.5-14.0). With the exception of HLA-B7 and HLA-DRB1*11, these significant differences were also seen comparative to local HPV-16-positive cervical carcinoma patients (n = 114), suggesting a specific immunogenetic contribution that is independent of HPV-16 infection in high-grade vulval intraepithelial neoplasia. Such factors are important to the development of HPV vaccines for treatment of cervical and vulval neoplasia.     

Human papillomavirus type 16 E6 variants and HLA class II alleles among Japanese women with cervical cancer

The enhanced oncogenicity of particular human papillomavirus type 16 (HPV16) E6 variants is population-dependent, implying the involvement of additional genetic cofactors. This study was designed to investigate the association between E6 variants and human leukocyte antigen (HLA) polymorphism within a Japanese population. Fifty-seven women with HPV16-positive cervical cancer were analyzed for E6 sequence variation and its relationship to HLA class II alleles. Compared with local controls (n = 138) and published controls (n = 916), DRB1*1501 and DQB1*0602 frequencies were significantly increased among patients with HPV16 E6 prototype (n = 11). Additionally, DRB1*1502 was positively associated with a particular E6 variant designated D25E (n = 25), although we could not find a significant association between HLA class II alleles and L83V variants (n = 16). Our observations suggest that a specific match between E6 variant proteins and HLA types may contribute to HPV16-related cervical carcinogenesis.     

Major histocompatibility complex class II polymorphisms and risk of cervical cancer and human papillomavirus infection in Brazilian women.

Infection with high-risk human papillomavirus (HPV) is the major risk factor for the development of malignant lesions in the uterine cervix. Environmental, behavioral, and ill-defined genetic factors also have been implicated in the pathogenesis of this disease. Associations between human leukocyte antigens (HLAs) and cervical cancer, precursor lesions, and HPV infections have been reported in several populations. To verify whether HLA-DRB1, -DQA1, and -DQB1 diversity is related to cervical cancer in the Brazilian population, 161 cases and 257 controls were HLA typed. Variants of DQA1 and DQB1 promoter regions were also typed in 92 cases and 228 controls. Polymorphism in HLA genes and promoters was distinguished by PCR-based methods, and the magnitude of associations was determined by logistic regression analysis. DRB1*15 [confounder-adjusted odds ratio (OR), 2.24; 95% confidence interval (CI), 1.29-3.90], DRB1*1503 (OR, 2.52; 95% CI, 1.16-5.48), and haplotype DRB1*15-DQB1*0602 (OR, 2.04; 95% CI, 1.15-3.61) were positively associated with cervical cancer. When we considered only DR15 haplotypes that did not carry the DQB1*0602 allele, the risk attributed to DRB1*15 more than doubled. A negative association was found between DQB1*05 and cervical cancer (OR, 0.57; 95% CI, 0.35-0.92), and similar trends were observed for DQA1*0101/04, DRB1*0101, and DRB1*1302. HPV positivity among controls was associated with DRB1*1503 (OR, 4.60; 95% CI, 1.33-15.9), DRB1*0405 (OR, 6.21; 95% CI, 1.66-23.2), and DQB1*0602 (OR, 2.48; 95% CI, 1.06-5.80). We suggest that HLA class II polymorphisms are involved in genetic susceptibility to cervical cancer and HPV infection in a Brazilian population from an area with a high incidence of this neoplasia.