本文選題：高危型人乳頭狀瘤病毒 + 子宮頸癌�。� 參考：《北京協(xié)和醫(yī)學(xué)院》2017年博士論文

【摘要】：研究目的利用前瞻性隊(duì)列隨訪數(shù)據(jù)評估高危型人乳頭狀瘤病毒(high-risk human papillomavirus,hrHPV)基因型別和病毒DNA甲基化在預(yù)測子宮頸癌發(fā)病風(fēng)險(xiǎn)中的作用,為其應(yīng)用于HPV陽性人群的分流管理和癌前病變的隨訪監(jiān)測提供有力的科學(xué)證據(jù)。材料與方法基于在我國子宮頸癌高發(fā)區(qū)山西省襄垣縣建立的子宮頸癌篩查隊(duì)列(SPOCCSⅠ)中2005-2014年隨訪數(shù)據(jù),以年齡為41-51歲、具有完整子宮頸的1,742名女性作為研究對象,采用PCR為基礎(chǔ)的線性探針反向雜交技術(shù)(SPF10-LiPA)對HC2檢測結(jié)果陽性的既往細(xì)胞學(xué)標(biāo)本進(jìn)行HPV基因型別檢測;采用亞硫酸氫鹽-焦磷酸測序法對HPV16陽性標(biāo)本進(jìn)行病毒DNA L1區(qū)和長控制區(qū)(LCR)甲基化水平的定量檢測;以病理活檢結(jié)果為金標(biāo)準(zhǔn),判定隨訪過程中的疾病結(jié)局和疾病轉(zhuǎn)歸(逆轉(zhuǎn)、持續(xù)和進(jìn)展)情況。利用Kaplan-Meier方法估算不同型別hrHPV陽性者10年內(nèi)形成高度癌前病變及子宮頸癌的累積發(fā)病風(fēng)險(xiǎn),并采用Cox比例風(fēng)險(xiǎn)模型計(jì)算相應(yīng)的風(fēng)險(xiǎn)比,評估基因型別對HPV陽性人群風(fēng)險(xiǎn)分層的作用;利用Mann-WhitneyU檢驗(yàn)分析HPV16 L1和LCR區(qū)DNA甲基化水平與疾病轉(zhuǎn)歸的關(guān)聯(lián),評估病毒甲基化在預(yù)測疾病進(jìn)展中的作用。研究結(jié)果1.hrHPV基因型別預(yù)測子宮頸癌的累積發(fā)病風(fēng)險(xiǎn):(1)型別分布:隊(duì)列人群中最常見為HPV16和52型別,其他常見型別按降序排列依次為58、33、18、51、31和56,HPV16感染率在隨訪過程中有下降趨勢;(2)一次感染發(fā)病風(fēng)險(xiǎn):一次感染HPV16女性形成中度及以上宮頸上皮內(nèi)瘤樣病變(CIN2+)的風(fēng)險(xiǎn)最高,10年內(nèi)累積發(fā)病率為 47.8%(95%CI = 36.0%-58.7%),HPV31 與 HPV16 接近(46.3%,95%CI:19.6%-69.5%),其他發(fā)病風(fēng)險(xiǎn)較高的有HPV 58、39、33、18和52,風(fēng)險(xiǎn)最低的有HPV45,51,56,59和68;(3)多次感染發(fā)病風(fēng)險(xiǎn):HPV16、31、33和58感染后形成CIN2+的累積發(fā)病風(fēng)險(xiǎn)與感染次數(shù)有關(guān),隨著感染次數(shù)增加,累積發(fā)病風(fēng)險(xiǎn)增加(p0.001),其他高危型HPV并未發(fā)現(xiàn)相似規(guī)律;(4)篩查效力:HPV檢測中增加基因型別可提高CIN2+的累積檢出率,篩查效力最高的型別為HPV16、31和58,一次檢測可避免60.8%CIN2+發(fā)生;(5)型別特異性HPV伴不同病毒載量者持續(xù)感染的風(fēng)險(xiǎn):HPV16病毒載量與持續(xù)感染具有劑量效應(yīng)關(guān)系,高病毒載量組和中病毒載量組發(fā)生持續(xù)性感染的風(fēng)險(xiǎn)分別約為低病毒載量組的23倍和4倍;(6)不同病毒載量的特定型別HPV感染者的發(fā)病風(fēng)險(xiǎn):hrHPV感染者發(fā)生CIN2+的累積發(fā)病風(fēng)險(xiǎn)與病毒載量存在一定的劑量效應(yīng)關(guān)系,HP16/18高病毒載量組和中病毒載量組發(fā)生CIN2+的風(fēng)險(xiǎn)分別約為低病毒載量組的3倍和2倍,非16/18hrHPV感染者高病毒載量時(shí)發(fā)病風(fēng)險(xiǎn)與細(xì)胞學(xué)異常者相近。2.HPV16L1和LCR區(qū)甲基化預(yù)測宮頸病變轉(zhuǎn)歸:(1)橫斷面篩選CpG位點(diǎn):L1 區(qū) 12 個(gè)CpG 位點(diǎn)(5602、5608、5611、5617、5709、5726、5927、6367、6389、6457、6650、7034)和 LCR 區(qū) 2 個(gè) CpG 位點(diǎn)(7535 和 7553)甲基化水平與病變相關(guān)(所有p0.05);(2)不同CpG位點(diǎn)甲基化與疾病轉(zhuǎn)歸關(guān)系:L1區(qū)位點(diǎn)6650高甲基化對不同病變?nèi)巳旱募膊∵M(jìn)展具有預(yù)測作用;LCR區(qū)尚未發(fā)現(xiàn)穩(wěn)定位點(diǎn)可預(yù)測感染結(jié)局;(3)不同CpG位點(diǎn)間相關(guān)性:L1和LCR區(qū)基因片段中大多數(shù)核酸位置相近的CpG位點(diǎn)甲基化水平具有較強(qiáng)的相關(guān)性;(4)DNA甲基化與病毒載量相關(guān)性:無論病變程度,L1和LCR區(qū)大部分CpG位點(diǎn)的甲基化水平與病毒載量相關(guān)性不強(qiáng)。研究結(jié)論1.hrHPV基因型別引起子宮頸癌及癌前病變的累積發(fā)病風(fēng)險(xiǎn)不同,按順序依次為:HPV16、31、58、39、33、52、18、45、51、56、59、68,因此基因分型檢測分流HPV陽性人群是可行的,但如何轉(zhuǎn)診和隨訪尚需要結(jié)合不同國家對風(fēng)險(xiǎn)閾值的接受程度和經(jīng)濟(jì)承受能力而定。2.特定型別HPV多次感染后子宮頸癌和癌前病變的風(fēng)險(xiǎn)明顯增加,提示子宮頸癌定期篩檢和監(jiān)測是必要的,如若發(fā)現(xiàn)持續(xù)陽性者應(yīng)給予密切隨訪或轉(zhuǎn)診治療。3.HPV基因分型檢測應(yīng)用于子宮頸癌篩查時(shí),累積檢出子宮頸癌及癌前病變的效力隨HPV檢測型別的增加而增高,其中HPV16,31和58貢獻(xiàn)最大,這為“HPV基因分型技術(shù)為主導(dǎo)”的子宮頸癌篩查策略的制定提供技術(shù)參考。4.子宮頸癌及癌前病變的發(fā)病風(fēng)險(xiǎn)隨特定型別HPV感染者病毒載量的升高而升高。對于非16/18型別陽性者,在細(xì)胞學(xué)等分流措施不具備條件下,病毒載量可作為HPV陽性人群進(jìn)一步分流的參考依據(jù)。5.HPV16 DNA L1和LCR區(qū)不同CpG位點(diǎn)甲基化與疾病關(guān)聯(lián)模式不同,L1區(qū)部分CpG位點(diǎn)有助于識別疾病進(jìn)展的人群,可能作為HPV感染的分流標(biāo)志物,但仍需要大樣本人群的前瞻性驗(yàn)證。
[Abstract]:Objective to evaluate the role of high risk human papillomavirus (high-risk human papillomavirus, hrHPV) genotypes and viral DNA methylation in predicting the risk of cervical cancer by prospective cohort follow-up data to provide a powerful scientific evidence for its application in the management of HPV positive people and the follow-up monitoring of precancerous lesions. Materials and methods based on the 2005-2014 year follow-up data of the cervical cancer screening cohort (SPOCCS I) established in Xiangyuan County, Shanxi Province, the high incidence of cervical cancer in China, 1742 women with a complete cervix with age 41-51 years old and a PCR based linear probe reverse hybridization (SPF10-LiPA) for the detection of HC2 The positive cytological specimens were detected by HPV genotypes, and the HPV16 positive specimens were detected by the hydrogen sulphite pyrophosphoric acid sequencing method and the DNA L1 region and the long control region (LCR) methylation level. The pathological biopsy results were the gold standard to determine the outcome of the disease and the outcome of the disease (reversal, persistence and prognosis). The Kaplan-Meier method was used to estimate the cumulative risk of high precancerous lesions and cervical cancer in 10 years of different types of hrHPV positive individuals, and the corresponding risk ratio was calculated by the Cox proportional hazard model, and the risk stratification of HPV positive groups was evaluated by genetic types; and HPV16 L1 and LCR were analyzed by Mann-WhitneyU test. The association of the level of DNA methylation with the outcome of the disease to assess the role of the virus methylation in predicting the progression of the disease. Results 1.hrHPV genotypes predict the cumulative risk of cervical cancer: (1) type distribution: the most common types in the cohort are HPV16 and 52, and the other common types are in descending order of 58,33,18,51,31 and 56, HPV16 There was a downward trend in the infection rate during the follow-up period; (2) the risk of first infection: the highest risk of moderate and above cervical intraepithelial neoplasia (CIN2+) was formed in one infected HPV16 female, and the cumulative incidence was 47.8% (95%CI = 36.0%-58.7%) within 10 years, HPV31 was close to HPV16 (46.3%, 95%CI:19.6%-69.5%), and the other risk was higher in HP. V 58,39,33,18 and 52, the lowest risk was HPV45,51,56,59 and 68; (3) multiple infection risk: the cumulative incidence of CIN2+ after HPV16,31,33 and 58 infection was associated with the number of infection, increased risk of infection increased with the number of infections (p0.001), other high-risk HPV did not find similar rules; (4) screening effectiveness: HPV detection increased Genetic types can increase the cumulative detection rate of CIN2+, the highest screening effectiveness is HPV16,31 and 58, and one test can avoid 60.8%CIN2+; (5) the risk of persistent infection of the type specific HPV with different viral loads: the HPV16 viral load and the persistent infection have a dose effect relationship, the high viral load group and the medium viral load group take place. The risk of continuous infection was about 23 times and 4 times of the low viral load group; (6) the risk of HPV infection in the specific type of different viral load: the cumulative incidence of CIN2+ in the hrHPV infected people was in a dose effect relationship with the viral load, and the risk of CIN2+ in the HP16/18 HV load group and the medium virus load group was respectively. About 3 and 2 times that of the low viral load group, the risk of high viral load in non 16/18hrHPV infected people was similar to that of those with abnormal cytology,.2.HPV16L1 and LCR methylation was used to predict the outcome of cervical lesions: (1) cross sectional screening of CpG sites: 12 CpG loci (560256085611561757095726592763676389645766507034) and LCR area 2 in L1 region The level of methylation of CpG loci (7535 and 7553) was associated with pathological changes (all P0.05); (2) the relationship between methylation at different CpG loci and disease prognosis: L1 region 6650 methylation has a predictive effect on the disease progression in different diseased populations; the LCR region has not been found that the stable loci can pretest the infection outcome; (3) the correlation between different CpG loci: L1 and LCR area The level of methylation of most CpG loci in the gene fragment has strong correlation. (4) the correlation between DNA methylation and viral load: no matter the degree of pathological changes, the level of methylation in most of the CpG loci in L1 and LCR regions is not associated with the viral load. Conclusions 1.hrHPV genotypes cause cervical cancer and precancerous lesions. The risk of cumulative incidence is different in sequence: HPV16,31,58,39,33,52,18,45,51,56,59,68, so it is feasible to detect the HPV positive group by genotyping, but how to transfer and follow up the risk threshold and the economic tolerance of different countries should be determined by the.2. specific type HPV after multiple infection of the cervical cancer and the cervical cancer. The risk of precancerous lesions is significantly increased, suggesting that regular screening and monitoring of cervical cancer is necessary. If persistent positive persons should be given close follow-up or referral for.3.HPV genotyping for cervical cancer screening, the cumulative effect of cumulative detection of cervical cancer and precancerous lesions increases with the increase of HPV type, HPV1 6,31 and 58 contribute the most. This provides a technical reference for the formulation of cervical cancer screening strategies based on HPV genotyping technology. The risk of.4. cervical cancer and precancerous lesions increases with the increase of viral load in patients with specific stereotyped HPV infection. For non 16/18 type positive individuals, the cytological shunt measures are not available. The viral load can be used as a reference for the further shunt of HPV positive people. The.5.HPV16 DNA L1 and the different CpG locus methylation patterns in LCR region are different from those of the disease. The partial CpG loci of the L1 region are helpful to identify the population of the disease progression, which may be the distributary marker of the HPV infection, but the prospective verification of the large sample population is still needed.

【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R737.33

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