HPV16E7及HLA-DQB1基因多态性与新疆维吾尔族宫颈癌关系研究
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摘要
目的：研究新疆维吾尔族妇女HPV16阳性子宫颈癌组织HPV16E7基因突变情况及子宫颈癌细胞表面HLA-DQB 1基因多态性与新疆维吾尔族妇女子宫颈癌关系。
方法：(1)采用聚合酶链反应(Polymerase chain reaction, PCR)方法对160例(子宫颈癌组80例,宫颈炎组80例)新疆维吾尔族妇女宫颈组织标本进行HPV16 E7基因扩增,电泳PCR产物确定扩增产物是否为E7片段,回收PCR产物并进行碱基测序。(2)采用反向膜杂交技术对80例宫颈鳞癌组织标本进行HPV分型。(3)运用聚合酶链反应-直接测序分型(Polymerase chain reaction-Sequencing Based Typing, PCR-SBT)扩增宫颈鳞癌及宫颈炎组织中HLA-DQB 1第二外显子,回收扩增产物并进行碱基序列测定分型。
结果：(1)54例宫颈鳞癌中共有6例发生HPV16 E7碱基突变,突变位点为：A647G(2/54),T760C (2/54),G663A (1/54),G666A (1/54),C790T (1/54),T846C (1/54),其中A647G(2/54)及C790T(1/54)为错义突变,分别导致第29位氨基由天冬酰胺变为丝氨酸及第77位氨基由精氨酸变为半胱氨酸。宫颈炎组中有2例HPV16 E7 PCR扩增阳性,测序未发现突变。(2)160个样本中共检测出296个等位基因,其中杂合的等位基因型136人份,纯合的等位基因型24人份。经过频率计算和统计分析发现HLA-DQB1*0325 (OR:10.60,1.341-83.81) HLA-DQB1*0332(OR:12.59,2.909-54.526)在新疆维吾尔族妇女宫颈鳞癌中频率明显高于宫颈炎对照组(p<0.05),而HLA-DQB 1*0317(OR:0.49,0.304-0.798)和HLA-DQB 1*040302 (OR:0.40,0.243-0.658)明显低于宫颈炎对照组(p<0.05)。(3)在80例宫颈鳞癌分型检测中,共检出15种高危型HPV(分别为HPV16,18,31,33,35,39,45,51,52,56,58,59,68,53,73),2种低危型HPV(分别为HPV11,42),其中HPV16单一感染33例,占44%；HPV16合并其他高危型感染20例,占26%,合并高危型感染的型别中以56型为主,占14例(70%),其次为33型、58型；HPV16合并其他低危型感染7例。80例子宫颈癌中有HPV16型感染的为62例,感染率为77.5%。在混合感染中以双重感染为多,其次为三重感染,发现1例为五重感染。
结论：(1)新疆维吾尔族妇女子宫颈癌中HPV感染以HPV16感染率最高,其次为HPV56,而HPV18型较少,且重复感染相对较多,与我国其他地区以HPV16、18型为主有差异,这为HPV疫苗在新疆维吾尔族聚集地区的开发提供一定的理论依据。(2)新疆维吾尔族妇女子宫颈癌HPV16 E7相对于我国其他地区、民族子宫颈癌具有高度保守性,这可能是导致新疆维吾尔族聚集区子宫颈癌高发的重要原因之一。(3)HLA-DQB 1*0325和HLA-DQB1*0332可能是新疆维吾尔族妇女子宫颈癌的易感基因,而HLA-DQB1*0317和HLA-DQB1*040302可能为新疆维吾尔族妇女子宫颈癌的保护基因。(4)HPV16 E7变异位点未发现DQ2抗原结合位点突变,这说明可能E7的变异并不是导致HLA抗原提呈能力下降的原因,某些HLA等位基因频率的升高和降低可能导致了HLA抗原提呈能力下降,这可能是新疆维吾尔族妇女子宫颈癌高发重要原因之一。
Objective:To research the relationship of HPV16E7 gene mutation in HPV16-positive cervical cancer and its cell surface HLA-DQB1 gene polymorphism in Xinjiang Uigur women uterine cervix cancer.
Method:(1)To copy the HPV 16 E gene for 160 cases (cervical cancer group 80 cases, cervicitis group 80 cases) of cervical tissue of Uygur women in Xinjiang by polymerase chain reaction method. By the use of gel electrophoresis, we determined whether the PCR amplification products were the E7 fragment. Then PCR products were recovered and its nucleotide sequences were detected. (2) The HPV of 80 cases Cervical cancer specimens were type by the reverse membrane hybridization. (3)Both the tissue specimens of cervical cancer and cervicitis second exon were copied by the Polymerase chain reaction-Sequencing Based Typing. The PCR products were recovered, sequenced and typied.
Result:(1)Among 54 cases of cervical cancer,6 cases were mutated in HPV16 E7 gene. The mutation sites were A647G(2/54), T760C(2/54), G663A(1/54),G666A(1/54),C790T(1/54)and T846C(1/54), A647G(2/54) and C790T(1/54) missense mutation. The mutation of A647G(2/54) lead the asparagine into serine at 29th site. The mutation of C790T(1/54) lead the arginine into cysteine at 77th site. Only 2 cases was not mutation in HPV16 E7 about cervicitis group. (2)296 alleles were found in 160 cases.136 alleles were heterozygous alleles,24 alleles were homozygous alleles. We found that HLA-DQB1*0325(OR:10.60,1.341-83.81) and HLA-DQB1*0332(OR:12.59,2.909-54.526) in cervical cancer group were more high than cervicitis group by frequency calculation and statistical analysis(P<0.05),but HLA-DQB1*0317(OR:0.49,0.304-0.798) and HLA-DQB1*040302(OR:0.40,0.243-0.658) in cervical cancer group were more low(P<0.05).(3) We found 15 kinds of high-risk and 2 kinds of low-risk HPV by genotyping in 80 cases of cervical cancer. The high-risk were HPV16,18,31,33,35,39,45,51,52,56,58,59,68,53,73.The low-risk were HPV(HPV11,42). In all infection cases,33 cases were only HPV16 infection,the percentage is 44% of all cases.20 cases were HPV 16 combination with other high-risk HPVs infection, the percentage is 26% of all cases. The first high-risk is HPV56(70% of all high-risk),the second and third were HPV58 and HPV33. Only 7 cases were HPV 16 combination with other low-risk HPVs infection. In cervicitis group,62 cases were infected by HPV 16, the percentage is 77.5% of all cases. The main infection was dual infection in the mixed infection, the second was triple infection,1 case was five infected.
Conclusion:(1) In Xinjiang Uygur women cervical cancer, the highest HPV infection is HPV16, the second is HPV56, HPV 18 infection is particularly low. This is different to the other area, where the main HPV infection are HPV16 and HPV 18. The difference provide a theoretical basis for developing a new HPV vaccine in Xinjiang where uighur reside. Compared to women in other parts of China or other national of China, Xinjiang Uygur cervical cancer women's HPV16 E7 is highly conserved. This was the most important cause which leaded cervical cancer is very high in Xinjiang Uygur women. (3) HLA-DQB1*0325 and HLA-DQB1*0332 probably are Xinjiang Uygur cervical cancer women's susceptibility gene. But HLA-DQB1*0317 and HLA-DQB1*040302 are protective genes possibly. (4) We found that antigen binding sites of DQ2 have not mutate in the variable sites of HPV16 E7. This reminds that the variation of E7 is not the cause which leaded the low antigen-presenting ability of HLA. The high and low frequency of HLA allele may leaded to the low antigen-presenting ability of HLA. This is the very important reason of high rate of cervical cancer in Xinjiang Uygur women.
方法：(1)采用聚合酶链反应(Polymerase chain reaction, PCR)方法对160例(子宫颈癌组80例,宫颈炎组80例)新疆维吾尔族妇女宫颈组织标本进行HPV16 E7基因扩增,电泳PCR产物确定扩增产物是否为E7片段,回收PCR产物并进行碱基测序。(2)采用反向膜杂交技术对80例宫颈鳞癌组织标本进行HPV分型。(3)运用聚合酶链反应-直接测序分型(Polymerase chain reaction-Sequencing Based Typing, PCR-SBT)扩增宫颈鳞癌及宫颈炎组织中HLA-DQB 1第二外显子,回收扩增产物并进行碱基序列测定分型。
结果：(1)54例宫颈鳞癌中共有6例发生HPV16 E7碱基突变,突变位点为：A647G(2/54),T760C (2/54),G663A (1/54),G666A (1/54),C790T (1/54),T846C (1/54),其中A647G(2/54)及C790T(1/54)为错义突变,分别导致第29位氨基由天冬酰胺变为丝氨酸及第77位氨基由精氨酸变为半胱氨酸。宫颈炎组中有2例HPV16 E7 PCR扩增阳性,测序未发现突变。(2)160个样本中共检测出296个等位基因,其中杂合的等位基因型136人份,纯合的等位基因型24人份。经过频率计算和统计分析发现HLA-DQB1*0325 (OR:10.60,1.341-83.81) HLA-DQB1*0332(OR:12.59,2.909-54.526)在新疆维吾尔族妇女宫颈鳞癌中频率明显高于宫颈炎对照组(p<0.05),而HLA-DQB 1*0317(OR:0.49,0.304-0.798)和HLA-DQB 1*040302 (OR:0.40,0.243-0.658)明显低于宫颈炎对照组(p<0.05)。(3)在80例宫颈鳞癌分型检测中,共检出15种高危型HPV(分别为HPV16,18,31,33,35,39,45,51,52,56,58,59,68,53,73),2种低危型HPV(分别为HPV11,42),其中HPV16单一感染33例,占44%；HPV16合并其他高危型感染20例,占26%,合并高危型感染的型别中以56型为主,占14例(70%),其次为33型、58型；HPV16合并其他低危型感染7例。80例子宫颈癌中有HPV16型感染的为62例,感染率为77.5%。在混合感染中以双重感染为多,其次为三重感染,发现1例为五重感染。
结论：(1)新疆维吾尔族妇女子宫颈癌中HPV感染以HPV16感染率最高,其次为HPV56,而HPV18型较少,且重复感染相对较多,与我国其他地区以HPV16、18型为主有差异,这为HPV疫苗在新疆维吾尔族聚集地区的开发提供一定的理论依据。(2)新疆维吾尔族妇女子宫颈癌HPV16 E7相对于我国其他地区、民族子宫颈癌具有高度保守性,这可能是导致新疆维吾尔族聚集区子宫颈癌高发的重要原因之一。(3)HLA-DQB 1*0325和HLA-DQB1*0332可能是新疆维吾尔族妇女子宫颈癌的易感基因,而HLA-DQB1*0317和HLA-DQB1*040302可能为新疆维吾尔族妇女子宫颈癌的保护基因。(4)HPV16 E7变异位点未发现DQ2抗原结合位点突变,这说明可能E7的变异并不是导致HLA抗原提呈能力下降的原因,某些HLA等位基因频率的升高和降低可能导致了HLA抗原提呈能力下降,这可能是新疆维吾尔族妇女子宫颈癌高发重要原因之一。
Objective:To research the relationship of HPV16E7 gene mutation in HPV16-positive cervical cancer and its cell surface HLA-DQB1 gene polymorphism in Xinjiang Uigur women uterine cervix cancer.
Method:(1)To copy the HPV 16 E gene for 160 cases (cervical cancer group 80 cases, cervicitis group 80 cases) of cervical tissue of Uygur women in Xinjiang by polymerase chain reaction method. By the use of gel electrophoresis, we determined whether the PCR amplification products were the E7 fragment. Then PCR products were recovered and its nucleotide sequences were detected. (2) The HPV of 80 cases Cervical cancer specimens were type by the reverse membrane hybridization. (3)Both the tissue specimens of cervical cancer and cervicitis second exon were copied by the Polymerase chain reaction-Sequencing Based Typing. The PCR products were recovered, sequenced and typied.
Result:(1)Among 54 cases of cervical cancer,6 cases were mutated in HPV16 E7 gene. The mutation sites were A647G(2/54), T760C(2/54), G663A(1/54),G666A(1/54),C790T(1/54)and T846C(1/54), A647G(2/54) and C790T(1/54) missense mutation. The mutation of A647G(2/54) lead the asparagine into serine at 29th site. The mutation of C790T(1/54) lead the arginine into cysteine at 77th site. Only 2 cases was not mutation in HPV16 E7 about cervicitis group. (2)296 alleles were found in 160 cases.136 alleles were heterozygous alleles,24 alleles were homozygous alleles. We found that HLA-DQB1*0325(OR:10.60,1.341-83.81) and HLA-DQB1*0332(OR:12.59,2.909-54.526) in cervical cancer group were more high than cervicitis group by frequency calculation and statistical analysis(P<0.05),but HLA-DQB1*0317(OR:0.49,0.304-0.798) and HLA-DQB1*040302(OR:0.40,0.243-0.658) in cervical cancer group were more low(P<0.05).(3) We found 15 kinds of high-risk and 2 kinds of low-risk HPV by genotyping in 80 cases of cervical cancer. The high-risk were HPV16,18,31,33,35,39,45,51,52,56,58,59,68,53,73.The low-risk were HPV(HPV11,42). In all infection cases,33 cases were only HPV16 infection,the percentage is 44% of all cases.20 cases were HPV 16 combination with other high-risk HPVs infection, the percentage is 26% of all cases. The first high-risk is HPV56(70% of all high-risk),the second and third were HPV58 and HPV33. Only 7 cases were HPV 16 combination with other low-risk HPVs infection. In cervicitis group,62 cases were infected by HPV 16, the percentage is 77.5% of all cases. The main infection was dual infection in the mixed infection, the second was triple infection,1 case was five infected.
Conclusion:(1) In Xinjiang Uygur women cervical cancer, the highest HPV infection is HPV16, the second is HPV56, HPV 18 infection is particularly low. This is different to the other area, where the main HPV infection are HPV16 and HPV 18. The difference provide a theoretical basis for developing a new HPV vaccine in Xinjiang where uighur reside. Compared to women in other parts of China or other national of China, Xinjiang Uygur cervical cancer women's HPV16 E7 is highly conserved. This was the most important cause which leaded cervical cancer is very high in Xinjiang Uygur women. (3) HLA-DQB1*0325 and HLA-DQB1*0332 probably are Xinjiang Uygur cervical cancer women's susceptibility gene. But HLA-DQB1*0317 and HLA-DQB1*040302 are protective genes possibly. (4) We found that antigen binding sites of DQ2 have not mutate in the variable sites of HPV16 E7. This reminds that the variation of E7 is not the cause which leaded the low antigen-presenting ability of HLA. The high and low frequency of HLA allele may leaded to the low antigen-presenting ability of HLA. This is the very important reason of high rate of cervical cancer in Xinjiang Uygur women.
引文
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[41]Maciag PC, Schlecht NF, Souza PS, Franco EL, Villa LL, Petzl Erler ML. Major histocompatibility complex class Ⅱ polymorphisms and risk of cervical cancer and human papillomavirus infection in Brazilian women. Cancer Epidemiol Biomarkers Prev 2000;9:1183-1191.
[42]Montoya L, Saiz I, Rey G, Vela F, Clerici-Larradet N. Cervical carcinoma: human papillomavirus infection and HLA-associated risk factors in the Spanish population. Eur J Immunogenet 1998;25:329-337.
[43]Paul K.S. Chan, Jo L.K. Cheung, Tak-Hong Cheung HLA-DQB1 polymorphisms and risk for cervical cancer: A case-control study in a southern Chinese population Gynecologic Oncology 2007; 105:736-741.
[44]Beskow AH,Josefsson AM,Gyllensten UB.HLA class Ⅱ alleles associated with infection by HPV16 in cervical cancer insitu [J].Int J Cancer,2001;93(6):817-822.
[45]王晖,武大林,申啊东等华南、华北人群HLA-DQB1等位基因多态性.中华医学遗传学杂志200623(2)：238-239.
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[2]SeniorK.Cervical cancer research focuses on the HPV E7 gene[J].Lancet,2002,3(10):585
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[5]张燕玲,乔志强,李隆玉,等.宫颈癌及癌前病变患者人乳头瘤病毒感染率的临床分析.实用癌症杂志,2005,20(2)：161-163.
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[1]JoelM.Palefsky and ElizabethA.Holly.Molecular virology and epidemiology Of human PaPillomavirus and cervical cancer. Cancer EPi, Bio&Pre,1995,1:415-428
[2]SeniorK.Cervical cancer research focuses on the HPV E7 gene[J].Lancet,2002,3(10):585
[3]ManoS MM, KinneyWK, HurleyLB, et al.Identifying women with cervical neoPlasia:using human PaPillomavirus DNA testing for equivocal PaPanieolaou results.JAMA,1999, 281:1605-1610.
[4]Tsuda H, Hashiguehi Y, Nishimura S, et al.RelationshiP between HPV tyPing and abnormality of G1 cell cycle regulators in cervical neoplasm. Gynceol Oncol,2003, 91:476-485.
[5]张燕玲,乔志强,李隆玉,等.宫颈癌及癌前病变患者人乳头瘤病毒感染率的临床分析.实用癌症杂志,2005,20(2)：161-163.
[6]Abba MC, Mouron SA. Association of human Papillomavirus viral load with HPV 16 and high-grade intraepithelial lesion[J].Int J Gynecol Caneer,2003,13(2):154-158.
[7]Sun CA, Liu J F, Wu DM, et al. Viral load of high-risk human Papillomavirus in cervical squamous intraepithelial lesions.Int J Gynecol Obstet,2002,76(1):41-47
[8]Sun CA, Lai HC, Chang CC, et al.The significance of human Papillomavirus viral load in Predietion of histologic severity and size of sqaumous intraepithelial lesion of uterine cervix.Gyneeol Oneol,2001,83(1):95-99.
[9]AN HJ,Cho NH,Lee S Y,et al.Correlation of cervical carcinoma and Precancerous lesions with human PaPillomavirus(HPV) genotyPes detected with the HPV DNA chiP microarray method. Cancer,2003,97(7):1672-1680.
[10]WankR,Thomssen C.High risk ofsquamous cell carcinoma of the cervix for women with HLA-DQw3[J]. Nature,1991,352(6337):723-725
[11]RessingM, SetteA, BrandtRM, etal.Human CTL presented by human Papillomavirustype 16E6 and E7 identified through invivo and invitro immunogenieity studies of HLA-A*0201-binding PePtides.J Immunol,154(11):5934-43,1995
[12]Konya J, Diliner J.Immunity to oncogenic human papillomaviruses.Adv Caneer Res 2001;82:205-238.
[13]Akash M. Mehta.Ekaterina S. Association of antigen processing machinery and HLA class I defects with clinicopathological outcome in cervical carcinoma Cancer Immunol Immun other (2008)57:197-206
[14]Beskow AH, Josefsson AM, GyllenstenUB.HLA classⅡ alleles associated with infection By HPV 16 in cervical cancer in situ.Int J Cancer.2001;93:817-822
[15]Yuh-Cheng Yang,Tzu- Yang Chang,HLA-DRB Alleles and Cervical Squamous Cell Carcinoma:Experimental Study and Meta-Analysis American Society for Histocompatibility and Immuno genetics,2006.67,331-340
[16]Yuh-Cheng Yang,Tzu-Yang Chang,HLA-DRB Alleles and Cervical Squamous Cell Carcinoma:Experimental Study and Meta-Analysis American Society for Histocompatibility and Immuno genetics,2006.67,331-340
[17]heu BC, Chiou SH, Chang WC, et al.Integration of high-risk human Papillomavirus DNA correlates with HLA genotyPe aberration and reduced HLA classⅠ molecule expression in human cervical careinoma.Clin Immunol 2005:115(3):295-301.
[18]Van der Bur SH,ressing ME,Kwappenberg KM.et al.Natural T helper immunity against humman papillomavirus type 16(HPV16)E7-derived peptide epitopes in patients with HPV16-positive cervical lesions:identification of 3 humman lekocyte antigen classⅡ-restricted epitopes Int J cancer 200191(5):612-618.
[19]Zehbe I,Tachezy R, Mytilineos J,et al. Human papillomavius 16 E6 polymorphisms in cervical lesions fro different European populations and their correlation with human lukocyte antigen class Ⅱ hapotypes.Int J Cancer,2002,94(5):711-716