1、启东农村现场肝癌早筛早启东农村现场肝癌早筛早诊队列建设与应用诊队列建设与应用I.背背 景景2QDLCI CHEN JG6第一批第一批上海上海市市派遣赴启东县肿瘤科研派遣赴启东县肿瘤科研小小分队分队1971年年11月月队长为上海市肿瘤医院原副院队长为上海市肿瘤医院原副院长长俞鲁俞鲁谊谊，指指导员为导员为 上海市肿瘤医院的许维珍。上海市肿瘤医院的许维珍。队员合队员合计计13人，来自上海市肿人，来自上海市肿瘤瘤医院医院、上上海海中山医中山医 院、上院、上海海市肿瘤市肿瘤研研究所、究所、上上海第一海第一医医学院等学院等内内外科外科、妇科、护理、检验及卫生统计妇科、护理、检验及卫生统计专专业。业。X5
2、年年队长为江苏省人民医院副院队长为江苏省人民医院副院长长(当时称副主当时称副主任任)薛集安，指导薛集安，指导 员是江苏新医学院（现南京医科大学及南京中医药大学）员是江苏新医学院（现南京医科大学及南京中医药大学）的的 尹力。尹力。队员合计队员合计30人，来自省人民医院、省中医研究所、南京大人，来自省人民医院、省中医研究所、南京大 学、南通医学院（现南通大学）及附院、省地理研究所、中学、南通医学院（现南通大学）及附院、省地理研究所、中 科院南京土壤研究所、江苏新医学院、江苏农学院（现扬科院南京土壤研究所、江苏新医学院、江苏农学院（现扬州州 大学）、省农药研究所（扬州）、省地质水文大队等单大学）、省
3、农药研究所（扬州）、省地质水文大队等单位。位。QDLCI CHEN JG7第一批第一批江苏江苏省省启东科研医疗队启东科研医疗队1972年年10月月X5 年年QDLCI CHEN JG8ShanghaiMortality from Liver Cancer by Township:Jiangsu Province 50 per 105/yr25-fold change in HCC rate in 200 kmMedian age of liver cancer death is 45-50 yearsQidongChen JG,QDLCI9Chen JG,Zhang SW.Seminar Ca
4、ncer Biol.2011;21(1):59-69.0Factors Attributed toLiver CancerHepatitis B VirusAflatoxin B1Chen JG,QDLCI1主主要病要病因因Kensler TW,et al.Nature Rev Cancer,2003主要危险因素主要危险因素乙肝病毒乙肝病毒黄曲霉毒素黄曲霉毒素Crude Rate,ASR,Truncated Rate and Cummurative Ratefor Incidence of Leading Cancer Sites in Qidong,1972-2011部位部位SiteICD-
5、10位次位次Rank例数例数No.CasesCR (1/105)CASR (1/105)WASR (1/105)%截截缩率缩率 Trunc.Rate 35-64 (1/105)累累积积率率Cum.Rate0-640-74(%)(%)累累积危险积危险 Cum.Risk 0-74(%)肝 LiverC2212839863.1739.3250.7130.61119.064.005.285.15胃 StomachC1621540134.2616.2525.5916.6040.031.413.153.10肺 LungC33-3431534034.1215.7425.4116.5336.961.323.2
6、73.22结直肠ColonrectumC18-214603513.436.209.806.5014.360.511.161.15食管 EsophagusC15544149.824.187.084.769.030.320.880.88乳腺 BreastC50634527.684.656.133.7215.310.490.640.64胰腺 PancreasC25732797.293.295.363.537.440.260.670.66白血病 LeukemiaC91-95819304.293.473.922.084.810.250.360.36脑（CNS)BrainC70-72917853.972.
7、673.341.921.920.230.360.36膀胱 BladderC671016193.601.522.551.743.300.120.290.29NHLC82-85/961114723.271.962.651.594.270.170.300.30宫颈C531212112.691.502.101.314.390.150.230.23鼻咽C11138291.841.101.470.893.130.110.160.16多发性骨髓瘤C90147151.590.841.240.771.960.070.160.16皮肤其它C44157011.560.611.060.761.120.040.100.
8、10骨C40-41165941.320.821.080.641.570.070.120.12前列腺C61175311.180.390.760.570.350.010.080.08胆囊胆管C23-24185301.180.540.850.571.310.040.100.10卵巢C56194721.050.650.860.511.890.070.090.09小肠C17204100.910.420.660.440.920.030.070.07全部全部All 92780206.39110.80159.11100.00288.4410.1018.1916.63发发病水病水平平粗发病率标化发病率CASR
9、of leading cancer sites,Qidong110100Incidenceper 100 000Crude Incidence of leading cancer sitesLiverStomach LungColon-rectumEsophagusBreastPancreas1972 1977 1982 1987 1992 1997 2002 2007 2012YearLeukemia1101001972 1977 1982 1987 1992 1997 2002 2007 2012YearASR China per 100 000LiverStomachLungColon-
10、rectumEsophagusBreastPancreas LeukemiaII.早诊早治早诊早治13QDLCI CHEN JG14第1阶段：1970s采用甲胎蛋采用甲胎蛋白白（AFP）检检测测方方法法，在启东自，在启东自然然人人 群中检群中检测测 AFP 200多万人多万人次次，其中，其中普普查查近近180万人万人 次，检出肝次，检出肝癌癌1000多多例例，其，其中中早早期期(期期)病例病例达达 到到35%。这个这个阶段阶段解决解决了肝了肝癌早癌早期诊期诊断的断的问问题题，证证实实AFP 应用于现场的普应用于现场的普查查，其简其简便、便、易易行、行、敏敏感、特感、特异异。启东肝癌筛查工作的历
11、程QDLCI CHEN JG15第2阶段：1980s启东重启东重新新估价估价了了AFP 普普查的查的作作用用，认认为为 AFP 普普 查查的的关关键键取取决决于于普普查查对对象象、范范围围的的择择优优选选择择；因因 此此提提出出了了选选择择特特定定的的高高危危人人群群进进行行肝肝癌癌筛筛检检的的概概 念。在这个阶段，明确提出乙型肝炎表面抗念。在这个阶段，明确提出乙型肝炎表面抗原原（HBsAg）阳阳性性的的3059岁岁的男的男性性为为启东启东肝癌肝癌的的高危险人群高危险人群。启东肝癌筛查工作的历程6QDLCI CHEN JG1高风险人群FemaleMale30600（+）（-）General p
12、opulationHBsAgMale30-59 Yrs HBsAg(+)High risk pop.Sex 性别性别Age年龄年龄乙型肝炎表面抗原乙型肝炎表面抗原第3阶段：1990s选定启选定启东东40万人万人群群范围中的肝癌高危险人群进范围中的肝癌高危险人群进行行 了了周期性的筛查实周期性的筛查实践践，确立了肝癌高危险人群确立了肝癌高危险人群筛筛 检模式和可行方检模式和可行方案案。于。于“八八五五”期间对肝癌期间对肝癌高危高危 险人群模险人群模式式、现场实施方案以及周期性筛、现场实施方案以及周期性筛检的亚检的亚 临床平均滞溜时临床平均滞溜时间间、灵敏度和预测值及、灵敏度和预测值及普查的超普查
13、的超 前时及最佳筛检间隔等进行了前时及最佳筛检间隔等进行了评评价分价分析析。QDLCI CHEN JG17启东肝癌筛查工作的历程QDLCI CHEN JG18第4阶段：2005卫生部卫生部疾疾病控制病控制局局和中国和中国癌癌症基金症基金会会根根据据中中国国 癌症预防与控制规划纲癌症预防与控制规划纲要要（2004-2010年）年）的部的部 署署，会，会同同部分省部分省卫卫生厅共生厅共同同建立建立了了癌癌症早症早诊诊早早治治 示范基示范基地地，启动了癌症早诊早启动了癌症早诊早治治项项目目。江苏启东与广西扶绥作为全国肝癌早诊早治示江苏启东与广西扶绥作为全国肝癌早诊早治示范范基基 地，自地，自2007
14、年开展了以肝癌的早诊早治筛查工年开展了以肝癌的早诊早治筛查工作作。启东肝癌筛查工作的历程“肝癌早诊早治示范基肝癌早诊早治示范基地地”挂挂牌牌仪仪式式建立市建立市癌癌症早症早诊诊早治早治领领导小导小组组超超 前前 时时计算计算出出高年高年龄龄段段 (4459 岁岁)与与低年低年龄龄段段 (3044岁岁)的平均滞留时间的平均滞留时间(MST)值分别为值分别为 0.47年年和和 0.55 年年，总总的的超前超前时为时为 0.49 年年。用用AFP和超作为筛查手段，筛查相对和超作为筛查手段，筛查相对于于 未未 筛筛 查 的查 的 死死 亡 危亡 危 险险 度 显度 显 著著 下下 降降（OR 0.63
15、1），），筛筛查查可以可以降降低肝低肝癌癌死死亡亡的危的危险险。筛筛 检检 间间 隔隔用用Logistic 模型模型分分析连续析连续阴阴性筛查性筛查次次数及最数及最后后一一 次阴次阴性筛性筛查至查至病例病例诊断诊断的持的持续时续时间间(TSLT)：阴阴性性 筛查对肝癌死亡的保护效应随时间的推移而筛查对肝癌死亡的保护效应随时间的推移而逐逐步步 下下降降,至至阴性筛阴性筛检检后后1.5年左右消年左右消失失，说，说明明两两次次筛筛 查的间隔不能超过一年查的间隔不能超过一年半半。AFP一一次阴次阴性筛查性筛查后后，OR下下降至基降至基准准的的1020%左右左右;连续连续次次阴性阴性筛筛 查查后后,OR
16、值下降值下降至至基准基准的的12%。因因此此,连连续续2次阴次阴 性筛查性筛查后后可适当可适当延延长下次长下次筛筛检时检时间间。可可检检测的临床前测的临床前期期（DPP）经对经对前前瞻资料瞻资料统统计进行计进行再再抽样组抽样组成成病例病例对对照照,对最后一次阴性筛查至肝癌死亡的持续时间的对最后一次阴性筛查至肝癌死亡的持续时间的分分 析来确析来确定定DPP。结结果果当当DPP为为 14 个月时个月时,最最大大对对 数拟然数拟然值值达极达极大大,因此因此用用FP筛查筛查肝肝癌癌的的DPP为为14 个月个月,即应在病例诊断前一年半内进行筛即应在病例诊断前一年半内进行筛检检,效益最效益最佳佳；也说；也
17、说明明筛查可筛查可以以提前诊提前诊断断肝肝癌癌。Survival of liver cancer cases in screened (n=240)and control(n=108)groups (2 month prevalent cases excluded)0.00.20.40.60.81.001224364860M O NTHSCTRLSCREENEDSurvival probability24QDLCI CHEN JG25国家卫计国家卫计委委 癌症基金癌症基金会会 Early Diagnosis and Treatment for the Liver CancerCases Scr
18、eened from a Recent ProgramQidongYearPerson Times ScreenedNo.Cases*Detection Rate in Group AGroup AGroup B%No.%No.%20071 6161511.861173.331280.0020082 5762531.941664.001976.0020093 5673261.792784.383093.7520103 63827111.482592.592592.5920114 48120140.891575.001995.0020124 46520120.901785.001785.0020
19、134 22519130.901578.951789.4720144 3611170.50763.6411100.0020154 27017150.801694.1217100.00合计33 199186821.1214980.1116789.78Early Diag.Cases in Group AEarly Treatment Cases in Group A*Group A:Detected by screening;Group B:Found between the screening points.26III.队列应用队列应用27281.前前瞻瞻研研究队究队列列在筛查的基础上，开展肝
20、癌的前瞻研究29HBsAg Cohort and Person Years Followed up(1977-2007)AgeHBsAg CarrierHBsAg Non-carrier All.MFM+FMFM+FMFM+F15-338.0562.0900.01557.02782.04339.01895.03344.05239.020-920.01363.02283.04375.97259.611635.55295.98622.613918.525-1458.22222.43680.67044.211980.319024.58502.414202.722705.130-1817.32982.
21、24799.58986.815460.624447.410804.118442.829246.935-2118.43472.45590.810488.418306.228794.612606.821778.634385.440-2365.03943.66308.612206.321387.033593.314571.325330.739902.045-2251.33897.36148.613019.122661.835680.915270.426559.141829.550-1785.63232.25017.811742.420650.632393.013528.023882.737410.7
22、55-1398.32580.23978.510273.317816.028089.311671.620396.232067.860-1137.21896.03033.29109.915363.524473.410247.117259.527506.665-857.61474.52332.18080.013342.321422.38937.614816.823754.470+1389.52387.83777.316535.727026.143561.817925.229413.947339.1合计合计17836.430013.647850.0113419.0194036.0307455.0131
23、255.4224049.6355305.0HBsAg Carrier State and Liver Cancer by Period,Qidong,ChinaHBsAg(+)HBsAg(-)PeriodSexP-YrsNo.RateP-YrsNo.RateRR95%CIM1103041371.71476541633.5811.076.08-21.131977-1986F1279718140.6666598812.0111.714.84-31.12T2382759247.621142522421.0111.797.22-19.81M13402.283619.3075428.83951.7011
24、.988.09-18.001977-1998F21653.542193.96131982.71511.3717.069.27-33.13T35055.7125356.58207411.55426.0413.699.88-19.21M17836.4118661.57113419.06153.7812.308.96-17.041977-2007F30013.655183.25194036.03417.5210.466.70-16.54T47850.0173361.55307455.09530.9011.709.06-15.1932Age Specific Rates of Liver Cancer
25、in HBsAg Carriers and Non-Carriers110100100010000年龄)万 01/1 (率 病 发HBsAg(+)男男HBsAg(+)女女HBsAg(-)男男HBsAg(-)女女M 37.76F 10.46M3.07F1.00HBVChen JG,et al.Chin J Epidemiol,2010,31(7):721-726.25-30-35-40-45-50-55-60-65-70+AgeIncidence per 100000332.免免疫疫预预防防队队列列建立新生儿出生免疫队列开展随访研究34693047075639520658637376563772
26、535756761458146531518902000400060008000100001400012000Vaccinees&Controls per Year.19181984198519861987198819891990YearsControl 40,828Vaccinated 40,605HB Vaccination Study,1984-1990,QidongImmunization35Aimed to observe the final result of incidence rate of liver cancer by HBV vaccination in children3
27、6Cumulative mortality probability of liver diseases in the vaccination and control groups.373.基基因因突突变研变研究究利用筛查队列开展嵌式病例对照研究38Screening(A)and control(B)cohortsA 2554Year(1989)199019911992199319941995X=ScreeningXB 1346XXXX+1158 XXXXX3712X+5231869Blood samples were colle cted and st oredStudy design:siz
28、e and the times of screening examinations(X)36,000+men screened5581 HBsAg(+)SubjectsQidong Liver Cancer Cohort(1989-2003)667 Cases of Liver Cancer from the cohort536 Samples with sufficient serum volume(100 l)515 Cases deceased prior to 12-31-2003355(69%)DNA recovered from serum 295(83%)Mutation at
29、1762T/1764A83%of analyzable serum samples contained double mutation HBV DNAChen JG,et al.Acceleration to death from liver cancer in people with hepatitis B viral mutations detected in plasma by mass spectrometry.CEBP,2007,16(6):1213-1218.40657685708088748390788692828893P=0.012P=0.083P=0.068ENHANCED
30、RISK OF LIVER CANCER FROMHBV DOUBLE MUTATION(%POSITIVE)Mutations are more common in younger peopleDiamond Graph modeling from Li&Muoz,Am Statistician(2003)A higher prevalence of HBV mutations was observed in those who had shorter survival times after the determination of mutationChen JG,et al.CEBP,2
31、00541Box-percentile plots showing the distribution of number of the cyclesneeded to detect HBV 1762T/1764A mutation by HCC case/controls statusChen JG,QDLCI among 278 cases and 250 controls with mutation31病例对照图示病例组的HBV突 变水平在50%百分位 时是对照组的16倍Muoz A,Chen JG,Egner PA,et al.Carcinogenesis.2011,32(6):860-
32、865OR=6.72The level of the HBV mutation was 15-fold greater at 50th percentile in cases than in controls(P 40-fold)过过去去28年中年中，黄曲霉黄曲霉毒毒 素素的暴露的暴露已已 经经大大下大大下降降黄黄 曲曲 霉霉 毒毒 素素 白白 蛋蛋 白白 加加 合合 物物检检 不不 出出 样样 本本 的的 百百 分分 比比536.早早诊诊早早治队治队列列QDLCI CHEN JG54High Risk PopulationFemaleMale3060Age0（+）（-）General pop
33、ulationHBsAgSexMale30-59 Yrs HBsAg(+)High risk pop.性别性别年龄年龄乙型肝炎表面抗原乙型肝炎表面抗原5515581 HBsAg+ve screendfrom 50 000+residents56.Survival of liver cancer cases in screened(A:n=240)and control(B:n=108)groups0.00.20.40.60.81.001224364860M O N T H SC T R LS C R E E N E DSurvival probabilityStage I:6.0%Stage
34、I:29.6%Group B:Group A:(2 month prevalent cases excluded)Chen JG,Parkin DM,Chen QG,et al.J Med Screen.2003,10(4):204-209Early Diagnosis and Treatment for the Liver CancerCases Screened from a Recent ProgramQidongYearPerson Times ScreenedNo.Cases*Detection Rate in Group AGroup AGroup B%No.%No.%200716
35、161511.861173.331280.00200825762531.941664.001976.00200935673261.792784.383093.752010363827111.482592.592592.592011448120140.891575.001995.002012446520120.901785.001785.002013422519130.901578.951789.47201443611170.50763.6411100.002015427017150.801694.1217100.00合计33199186821.1214980.1116789.78Early D
36、iag.Cases in Group AEarly Treatment Cases in Group A*Group A:Detected by screening;Group B:Found between the screening points.57反复筛查发现肝癌病例与自助就诊发现病例生存率比反复筛查发现肝癌病例与自助就诊发现病例生存率比较较（2007-2015）58陈建国陈建国,等等.中华肿瘤杂志中华肿瘤杂志,发表中发表中IV.效果评价效果评价59Analysis of HBV Mutations in Plasma Samples of Liver Cancer Cases Pla
37、sma samples of adequate volume were available for 512 of the 667 liver cancer cases.HBV DNA was found in 371(72.5%)of 512 samples.Using mass spectrometry,mutations in HBV were determined and 294(79.2%)of these samples contained a two nucleotide 1762T/1764A mutation.37 of the 294 samples had an addit
38、ional double mutation in the HBV X-gene coding sequence.16 samples had novel mutations in the 1761 to 1767 region of the HBV genome.All detectable mutations were in the X-gene region.Mortality from Primary Liver Cancer per 100,0000.111010030-3425-2920-2410-1415-1935-3940-441938-421943-471953-571963-
39、671973-77 1983-87Five Year Birth Cohorts1993-9745-4950-5455-5960-64 years oldno vaccination1948-521958-621968-721978-82vaccination1988-92 1998-2002启东癌症启东癌症登记登记处资处资料料Data from Qidong Cancer RegistryMost of the decline in liver cancer has occurred in young and middle age birth cohortslikely vaccinated
40、 in 2002 as 5-10 year oldsperhaps 25%vaccinated大部分肝大部分肝 癌的下降癌的下降 出现在中出现在中 青青年年出生出生 队列中队列中Environmental Exposures are Associated with Declining Liver Cancer Mortality in Qidong环境暴露环境暴露物与物与启东肝癌启东肝癌死亡死亡率的下降率的下降有关有关Chen JG,Egner PA et al.CAPR 2013Different cohortsChen JG,QDLCI63Survival rateSurvival yea
41、rThe comparison of survival rates between screening cohort and general population in QidongThe difference(effectiveness)of early detection and treatment in the field secondary prevention practice.ScreeningcohortGeneral populationIs that because of lead Time of the screening？No!46ProvinceCity/county2
42、0062007 20082009 2010 2011 20122013 2014 2015江苏江苏Jiangsu启东启东 海门海门 湖北湖北Hubei公安公安 宜都宜都 英山英山 当阳当阳 洪湖洪湖 黄冈黄冈 嘉鱼嘉鱼 广西广西Guangxi扶绥扶绥 贵港贵港 岑溪岑溪 崇左崇左 武鸣武鸣 福建福建Fujian同安同安 柘荣柘荣 广东广东Guangdong中山中山 Liver Cancer Screening Program in ChinaCentral Financial Transfer Payment Project65FundsInternational collaboration,
43、National key grants,National/Provincial programs.ContentsChemoprevention trials,Biamarker studies,Risk factor measurement,Family pedigree studies,Twins genetic studies,Case-control studies,Screening programs,HB vaccination study,Special biobank program,etc.Source of SpecimensGeneral population or pa
44、rticipants of screening,High risk group with+ve/-ve HBsAg,Patients with liver cancer and their family members,Family members of twins,Vaccinees,Controls,etc.QuantitySerum 180 000,Plasma about 150 000,WBC 100 000,Tissue/paraffins of liver cancer 1 200,Urine 40 000.Specimens in Qidong BiobankFrom Cohortto BiabankTo collect useful specimens to set up biobank for the further study of precision medicine.谢谢 谢谢
