本文選題：人乳頭瘤病毒　切入點：鮑恩樣丘疹病　出處：《北京協和醫(yī)學院》2012年博士論文

【摘要】：尖銳濕疣(condyloma accuminatum CA)和鮑恩樣丘疹病bowenoid papulosis of vulva, BP),前者是皮膚科門診和性病門診最常見的性病,由高危HPV感染者有癌變可能；后者病理形態(tài)上有組織排列和細胞的異型性,被認為是一種低度惡性的病毒感染性皮膚病或癌前病變。 HPV感染可以引起不同的臨床表型,CA感染以低危型HPV為主,而BP感染的HPV以高危型為多。高危和低危型HPV感染的易感性在人群中是否有差異,感染高危低危型HPV之后其臨床表型是否和人群的基因多態(tài)性有關,值得研究。近年關于p53及其同家族的抑癌基因p73的多態(tài)性和HPV相關的腫瘤易感性研究逐漸增多。部分研究發(fā)現HPV相關腫瘤和p53codon72密碼子或p73第二外顯子第4和14位堿基的基因多態(tài)性有關。但不同地區(qū)和人群的研究結果不一致。 我們收集江蘇南京地區(qū)感染HPV的尖銳濕疣和鮑恩樣丘疹病患者的皮損和血樣,以及在性病門診進行健康體檢的性病高危人群為陰性對照,進行HPV分型以及HPV感染臨床表型和宿主p53、p73基因多態(tài)性的關系研究。初步探索不同HPV感染的臨床表現是否有不同,以及HPV易感性和宿主p53、p73基因多態(tài)性的相關性,為今后的研究做一定的參考。全文分三部分。 第一部分尖銳濕疣及鮑恩樣丘疹病中HPV病毒基因型與疾病臨床表現之間關系的研究 目的通過直接測序法對尖銳濕疣以及鮑恩樣丘疹病中HPV進行基因分型研究。根據測序所得到的型別,結合文獻中尖銳濕疣和鮑恩樣丘疹病中HPV的常見型別,分別設計型特異引物,通過特異性PCR來驗證和補充測序結果,以探討尖銳濕疣和鮑恩樣丘疹病中HPV的分子流行病學狀況。 方法通過直接測序法對收集到的尖銳濕疣和鮑恩樣丘疹病患者皮損中的HPV進行基因分型研究,根據測序得到的型別和文獻中的常見型別,設計特異性引物,通過型特異性PCR來驗證和補充測序結果,結合病例的臨床表現,分析HPV不同型別感染的臨床表現是否有不同。 結果共收集CA標本124例,BP標本14例.CA患者HR-HPV的發(fā)生率為6.03%(7/116),BP為50%(7/14),兩組比較,差異有統(tǒng)計學意義(X2=20.76P0.01)。這與既往文獻報道的BP以HPV-16感染為主一致。因此,臨床上懷疑BP的患者,除做病理確診外,建議行HPV型別檢測。感染HR-HPV的7例CA患者中,男性5例,女性2例；肛周3例,系帶旁1例,包皮1例,小陰唇2例；菜花狀5例,丘疹狀1例,乳頭樣1例。經統(tǒng)計,性別、部位、皮損形態(tài),與易感HR-HPV之間并無相關性, 結論我們對收集到的生殖器部位尖銳濕疣患者的HPV型別進行了鑒定,并對其皮損形態(tài)、皮損發(fā)生部位和感染HPV型別之間進行了統(tǒng)計學分析,發(fā)現前兩者和患者感染HPV型別之間統(tǒng)計學上并無顯著相關性。 第二部分尖銳濕疣和鮑恩樣丘疹病患者p53基因多態(tài)性分布的研究 目的收集尖銳濕疣和鮑恩樣丘疹病患者的血液標本,做p53多態(tài)性檢測,分析p53的72密碼子的基因改變與皮膚HPV感染的HPV型別、臨床表現的關系。 方法實驗組選取本院皮膚科門診2010年6月到2011年9月接受激光治療的尖銳濕疣患者及病理確診并接受激光治療的鮑恩樣丘疹病患者的血樣及皮損。陰性對照組來自本院性病科性病體檢排除尖銳濕疣的健康人群或患其他性病患者血樣。實驗組和對照組血樣做p53多態(tài)性檢測。結合患者皮損內感染HPV的型別,和實驗組對照組p53多態(tài)性結果,對數據結果進行統(tǒng)計學分析。 結果收集CA患者血樣116例,測序陽性112例,收集BP患者血樣14例,測序陽性14例。結果發(fā)現CA, BP患者體細胞有三種類型,CGC純合型,CCC純合型,CGC/CCC雜合型。CA組與對照組相比,Arg/Pro基因型者罹患CA的幾率較其他兩種純和型低。BP組三種基因型與BP患病率無顯著相關性(P0.05)。p53基因多態(tài)性與HPV高危和低危型易感性之間無顯著相關。 結論我們發(fā)現Arg/Pro基因型對罹患CA有保護性作用,但對同樣為HPV感染高度相關的BP則未發(fā)現顯著相關,將p53codon72Arg和Pro兩個等位基因的分布與感染HPV的類型作相關性分析,未發(fā)現顯著差異。究其原因,可能與我們所收集的BP病例數量較少有關,后續(xù)研究還需要進一步擴大樣本量,完善臨床數據,進一步進行研究。 第三部分尖銳濕疣和鮑恩樣丘疹病患者p73基因多態(tài)性分布及與HPV感染型別相關性的研究 目的將尖銳濕疣和鮑恩樣丘疹病患者的血液標本做p73多態(tài)性檢測,分析p73第二外顯子第4位和14位堿基的多態(tài)性與皮膚HPV感染的HPV型別、臨床表現的關系。 方法實驗組選取本院皮膚科門診2010年6月到2011年9月接受激光治療的尖銳濕疣患者及病理確診并接受激光治療的鮑恩樣丘疹病患者的血樣及皮損。陰性對照組來自本院性病科性病體檢排除尖銳濕疣的健康人群或患其他性病患者血樣。實驗組和對照組血樣做p73多態(tài)性檢測。結合患者皮損內感染HPV的型別,和實驗組對照組p73多態(tài)性結果,對數據結果進行統(tǒng)計學分析。 結果收集CA患者血樣90例測序陽性83例,BP患者血樣14例,測序陽性14例。結果發(fā)現BP、CA患者體細胞有A4T14/G4C14雜合型,A4T14純合型,G4C14純合型三種類型。p73第二外顯子GC、AT兩個等位基因的分布、與CA/BP相關性,以及與感染HPV的類型作相關性分析。在CA患者中GC和AT兩基因分布與對照組相比無明顯差異,BP患者中相比攜帶AT基因,攜帶GC基因則降低了BP的患病風險。與AT/AT基因相比,攜帶GC/AT和GC/GC基因降低了感染HPV患尖銳濕疣的風險。鮑恩樣丘疹病組與對照組相比,攜帶A4T14基因型的個體罹患BP的風險要高于攜帶G4C14者；相對A4T14/A4T14基因型,G4C14/G4C14基因型罹患BP的風險顯著降低；將G4C14/A4T14與G4C14/G4C14基因型相比,后者也有較低的罹患BP的風險。p73第二外顯子的等位基因和基因型分布與感染高危和低危型HPV之間未見顯著相關性。 結論攜帶AT基因增加了BP和CA的患病風險。A4T14/A4T14基因型和G4C14/A4T14基因型比G4C4/G4C4基因型罹患BP的風險增加；攜帶GC/AT和GC/GC基因比攜帶AT/AT基因者患尖銳濕疣的風險較低。p73第二外顯子的等位基因和基因型分布與CA和BP中高危和低危型HPV易感性之間在本次研究中未見顯著相關性。
[Abstract]:Condyloma Acuminatum CA and Bowen ' s papulosis , the former is the most common sexually transmitted disease in Dermatology Clinic and STD clinic , which may be caused by high - risk HPV infection .
The latter pathological form is characterized by tissue arrangement and cell differentiation , and is considered to be a low - degree malignant virus infectious skin disease or precancerous lesion .

HPV infection can lead to different clinical phenotypes , CA infection is mainly low - risk HPV , while the HPV of BP infection is high risk type . The susceptibility of HPV infection after high - risk and low - risk HPV infection is related to the polymorphism of human gene polymorphism . In recent years , it has been found that HPV - related tumor and p53codon72 codon or p73 - second exon 4 and 14 - base gene polymorphism are related . However , the results of different regions and population are inconsistent .

We collected lesions and blood samples from patients with HPV infection in Nanjing , Jiangsu Province , as well as the relationship between HPV typing and clinical phenotype of HPV infection and p53 and p73 gene polymorphism in STD clinic .

Study on the relationship between HPV genotypes and clinical manifestations in first partial condyloma and Bowen - like papulosis

Objective To study the genotyping of HPV in patients with condyloma and Bowen ' s papulosis by direct sequencing . According to the type of HPV in the literature , specific primers were designed to verify and complement the sequencing results by specific PCR to investigate the molecular epidemiology of HPV in Condyloma Acuminatum and Bowen - like papulosis .

Methods HPV types in lesions of patients with condyloma and Bowen - like papulosis were analyzed by direct sequencing . Specific primers were designed according to the types of sequencing and the common types in the literature . The results of sequencing were verified and supplemented by typing specific PCR . The clinical manifestations of the cases were analyzed .

Results The incidence of HR - HPV was 6.03 % ( 7 / 116 ) , BP was 50 % ( 7 / 14 ) .
3 cases were perianal , 1 case was near the frenulum , 1 case was covered , 2 cases were small .
There were 5 cases of cauliflower , 1 case of papule , 1 case of nipple , and no correlation was found between statistic , sex , site , lesion morphology and susceptibility HR - HPV .

Conclusion The HPV types of patients with genital area of genital area were identified , and the morphology , location of lesions and HPV types were analyzed statistically . There was no statistically significant correlation between the HPV types before and after the detection of HPV types .

Study on p53 gene polymorphism in the second part of patients with Condyloma Acuminatum and Bowen - like papulosis

Objective To investigate the relationship between the changes of p53 gene and HPV type and clinical manifestation of HPV infection in patients with condyloma and Bowen - like papulosis .

Methods The blood samples and skin lesions of the patients who were diagnosed and treated with laser were selected from the dermatological department of our hospital from June 2010 to September 2011 .

Results There were 116 cases of blood samples collected from CA patients , 112 cases were sequenced , 14 cases were collected from BP and 14 cases were sequenced .

Conclusion We find that the Arg / Pro genotype has protective effect on CA , but there is no significant correlation between the distribution of p53codon72Arg and Pro two alleles and the type of infected HPV . There is no significant difference between the distribution of p53codon72Arg and Pro .

The distribution of p73 gene polymorphism in patients with third partial condyloma and Bowen - like papulosis and its correlation with HPV infection

Objective To investigate the polymorphism of p73 gene exon 4 and 14 base and the relationship between HPV type and clinical manifestation of HPV infection .

Methods The blood samples and skin lesions of the patients who received laser therapy from June 2010 to September 2011 were selected from the experimental group . The negative control group received blood samples from the healthy population or patients with other sexually transmitted diseases . The control group and the control group were tested for p73 polymorphism .

Results There were 83 cases of blood sample in CA patients , 14 cases of BP and 14 cases of sequencing . The results showed that there was no significant difference between the two alleles of the two alleles in the patients with CA , the correlation between the two alleles of A4T14 / G4C14 , the correlation with CA / BP and the type of infected HPV .
Compared with A4T14 / A4T14 genotype , the risk of G4C14 / G4C14 genotype was significantly lower than that of A4T14 / A4T14 .
Comparing G4C14 / A4T14 with G4C14 / G4C14 genotype , the latter also had lower risk of BP . The allele and genotype distribution of p73 second exon was not significantly correlated with high - risk and low - risk HPV infection .

Conclusion The genotypes of A4T14 / A4T14 and G4C14 / A4T14 were higher than those of G4C4 / G4C4 genotype .
There was no significant correlation between allele and genotype distribution of p73 second exon and high - risk and low - risk HPV susceptibility in CA and BP .

【學位授予單位】：北京協和醫(yī)學院
【學位級別】：博士
【學位授予年份】：2012
【分類號】：R752.53

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本文編號：1725972