恶性肿瘤流行病学精品课件

Department of Epidemiology Public Health College of Harbin Medical University 恶性肿瘤流行病学 Epidemiology of Cancer 哈尔滨医科大学流行病学教研室 Department of epidemiology ，Harbin Medical University Department of Epidemiology Public Health College of Harbin Medical University 恶性肿瘤(Cancer)是一组严重威胁人类健康的 疾病，由100多种不同部位肿瘤组成。近年来，恶性 肿瘤的总体发病情况在世界各国多呈上升趋势，但 其中个别癌种在部分国家和人群中有所下降。估计 到2015年，全世界肿瘤死亡者可达900万，发病者可 达1500万，其中三分之二将发生在发展中国家。 现 况 （Status） In 2015：15x106 people suffer from cancer 2/3 in developing country Motility will reach to 9x106 Department of Epidemiology Public Health College of Harbin Medical University 概述 (Introduction) 恶性肿瘤流行病学研究方法 (Study method of epidemiology) 全球恶性肿瘤流行状况 (Prevelence states) Department of Epidemiology Public Health College of Harbin Medical University 我国主要恶性肿瘤流行状况 (Cancer prevelence of China) 恶性肿瘤的危险因素 (Risk factors of cancer) 恶性肿瘤的预防 (Prevention of cancer) Department of Epidemiology Public Health College of Harbin Medical University 恶性肿瘤流行病学主要研究恶性肿瘤在 人群的分布及其影响因素，探索病因，制 定相应的防治措施并对这些措施加以评价 。 概念(Concept) Department of Epidemiology Public Health College of Harbin Medical University Definition (1) Cancer epidemiology is the study of the pattern of cancer in populations. (2) Its essential aim is to identify causes of cancer, including preventable (avoidable) causes and inherited tumor susceptibility. Department of Epidemiology Public Health College of Harbin Medical University (3) It is also play an critical role in many other areas of cancer research including evaluation of screening effects, cancer prevention and control (4) Current studies directions includes molecular and genetic epidemiology of cancer. Department of Epidemiology Public Health College of Harbin Medical University 第一节 概 述 (Introduction) 一 、基本概念 肿瘤是指生长于某种器官但却与该 靶器官不相协调的组织团块的异常增生 。 Department of Epidemiology Public Health College of Harbin Medical University Department of Epidemiology Public Health College of Harbin Medical University 1.恶性肿瘤的病理学特点 (Pathological Features ) 1）细胞(cell): 肿瘤细胞与正常细胞的区别 在于肿瘤细胞分化功(differentiation)降低 或丧失，分化程度降低是恶性肿瘤的个性特 征，称为间变。 Department of Epidemiology Public Health College of Harbin Medical University 分子病理学技术包括免疫组化和DNA检测 技术的发展促进了肿瘤临床治疗、预防和病因 学研究的发展。 免疫组化方法通过对荧光标记的肿瘤特异 性抗原抗体结合物的测定来进行肿瘤分类，区 分原发或转移性肿瘤，检测肿瘤临床特征和预 后生物标记等。如p53蛋白的过度表达可以提示 肿瘤的多耐药特性。 Molecular pathologic Technology and immune chemistry methods DNA检测技术的发展也促进了癌 症基因诊断技术的发展，目前已有 可能通过检测外周血或组织中的特 异性基因来诊断某些癌症 DNA Technique 2）生物标志（Biomarker）指的 是能代表生物结构和功能的可识别物 质，对生物标志的测量可发现机体在 遗传、细胞和分子水平发生的改变。 Department of Epidemiology Public Health College of Harbin Medical University 3）肿瘤的病理分期和分级(classification) 国际抗癌联盟根据原发肿瘤的大小及范围（ T），局部淋巴结（N）受累情况以及肿瘤转移情 况（M）3项指标对肿瘤进行病理学分期，简称 pTNM分期。 其中T描述原发肿瘤的定位和大小，N代表局部 淋巴结转移情况，M表示有无远距离转移。 Department of Epidemiology Public Health College of Harbin Medical University Department of Epidemiology Public Health College of Harbin Medical University 恶性肿瘤的分级（classification）可表 明恶性肿瘤的恶性程度,通常根据肿瘤细胞和 组织结果的分化程度、异型程度、核分裂多寡 、肿瘤的类型等来判断，迄今没有统一的分级 方法。 国际上现在普遍采用的是3级分类法， 级表示高度分化，表示中度分化，表示低 度分化。不同种类的肿瘤，如鳞癌、腺癌、肉 瘤等其3级分类都有详细的病理学标准。 Department of Epidemiology Public Health College of Harbin Medical University 2.恶性肿瘤细胞的生物学特点 (Biological characteristics) 基因表达(gene expression)和细胞 周期(Cell cycle )的调控是某些蛋白质来 完成的，负责这些蛋白质编码的基因的自发 性或遗传获得性突变导致了癌症的发生。 Department of Epidemiology Public Health College of Harbin Medical University 肿瘤的生物学特征 (Biological characteristics) 细胞类型 核型 生长 接触抑制 锚定 正常细胞 小 可控 癌细胞 大 失控 肿瘤细胞具有永生性(Immortality )，侵袭性 (Invasiveness)，扩散性(Spreading ) Department of Epidemiology Public Health College of Harbin Medical University 肿瘤细胞的起源 (Origin of tumor) 单克隆起源（Monoclonal theory） 一个肿瘤的细胞群体源于一个转化单细胞 的不断增殖而成。而这个单细胞是具有分化和 增殖的干细胞（stem-cell）。对细胞群的遗 传标记分析，具有高度一致性 例如： 多灶 性细支气管肺泡癌（BAC），原发灶，卫星灶 ，转移灶中的不同区域的癌细胞k-ras具有相 同的突变。 Department of Epidemiology Public Health College of Harbin Medical University 肿瘤细胞群是由多个肿瘤克隆发展而来。 鼠肠肿瘤细胞的基因分析(Genetic analysis )： 在肿瘤的不同区域取样的细胞，在APC基因和Mshz 基因具有不同的缺失。 多克隆起源（Polyclonal theory） Department of Epidemiology Public Health College of Harbin Medical University 单中心发源和多中心发源 p单中心发源（单性灶） 肿瘤源于原始的一簇细胞。从原位灶到浸润灶 转移灶,复发灶都由第一代肿瘤细胞而来。 p多中心发源（多灶性） 肿瘤源于不同区域的多簇细胞。原位灶，癌旁 浸润灶,对器官,系统器官肿瘤细胞有不同程度 的异型。 p分子生物学实验支持单中心起源。 (Origin of Single center or Multi center) Department of Epidemiology Public Health College of Harbin Medical University 癌基因 (Oncogene) p能在体外引起细胞转化，在体内诱发肿瘤的基因 . p细胞内的原癌基因高度保留，从酵母到人都存在 ，这些基因与细胞生长，增殖，分化有关，并受 到精细和严格的控制。 p原癌基因具有的生物学功能：在正常细胞中，负 责调控基因表达、DNA复制、细胞分裂和细胞死 亡的基因。 Department of Epidemiology Public Health College of Harbin Medical University 癌基因发现 (Discovery of oncogene) p1911年 Rous发现鸡肉瘤病毒（RSV）能使鸡胚 成纤维细胞转化，也能使鸡诱发肿瘤。 p1976年从RVS病毒中发现了src癌基因。克隆了 该基因，是第一个Vonc。 p1982年从人膀胱癌细胞中分离出了细胞癌基因 ras基因。是第一个 C-onc。 Department of Epidemiology Public Health College of Harbin Medical University 细胞癌基因(c-onc) p1976年，Bishop从Rous病毒中分离出癌基因 src,并在动物正常细胞中发现有同源序列。以 后在许多病毒癌基因都在细胞中都发现了它的 同源序列，这些序列被称为细胞癌基因。 p病毒癌基因源于细胞癌基因。 Department of Epidemiology Public Health College of Harbin Medical University 癌基因致癌机制 (Mechanisms ) 点突变 原癌基因ras 编码189个氨基酸的蛋白是一个细胞信号 传导中起着开关作用的蛋白，当ras gene 突变时 ,ras 蛋白一直处于开的状态，细胞生长。 ras proto-oncogene 1 12 61 189 gly gln arg ( G C), k-ras oncogene 癌基因的种类 (Types of Oncogene) pabl pbcl perb pfos pmyc pras psis psrc 等100多种。 Department of Epidemiology Public Health College of Harbin Medical University 癌基因作用位置 Gene c-onc protein v-onc protein src 膜 膜 ras 膜 膜 myc 核 核 fps 质 质和膜 abl 核 质 (Sites of oncogene) Department of Epidemiology Public Health College of Harbin Medical University 癌基因的肿瘤诱发机制 (Mechanism of Oncogene) p癌基因突变 ras的第12个密码子突变，GT argval, ras蛋白与GTP结合， 促进了细胞的生长。 pras 附近插入了启动子，启动癌基因表达。 pras的CCGG甲基化程度降低，癌基因异常高表达 。 Department of Epidemiology Public Health College of Harbin Medical University ras 癌基因家族 根据不同时期，不同组织的癌基因表达，将ras基 因家族分为三类： H-ras 11p15.5 胃癌 膀胱癌 宫颈癌 N-ras 1p13.2 白血病 肝癌 K-ras 12p12.1 胰腺癌 肺癌结 肠癌 (Family members of ras) Department of Epidemiology Public Health College of Harbin Medical University 致癌病毒 (Cancer-inducing virus) 病 毒 核酸结构 癌基因 乳多空病毒 环状双链DNA T抗原基因 腺病毒 线状双链DNA E1A，E1B 疱疹病毒 线状双链DNA EB序列 反转录病毒 单链RNA ras,src等 Department of Epidemiology Public Health College of Harbin Medical University 肿瘤抑制基因（tumor suppressor gene） 一类与细胞周期调控有关的基因，当这些基因正常表达 时，具有抑制细胞分裂的功能。这些基因的失活或缺失 ，会导致细胞非正常的分裂，正常细胞有可能转化为肿 瘤细胞。 1968年Harris实验： 癌细胞系 X 正常细胞 无恶性表型细胞 正常 癌细胞 （染色体部分丢失） Department of Epidemiology Public Health College of Harbin Medical University 首先发现的肿瘤抑制基因 (First discovered Tumor Suppressor Gene) 视网膜母细胞瘤 发现Rb基因缺失呈杂合体时，细胞是正常 的，缺失纯合体时细胞转化。显示该基因是纯 合隐性致癌。Rb纯合缺失后致癌表明Rb基因存 在时对肿瘤细胞有抑制作用，因此Rb是肿瘤抑 制基因。 del(13) (q14) Department of Epidemiology Public Health College of Harbin Medical University 二、恶性肿瘤流行病学研究方法 (Study methods of Cancer Epidemiology) 经典流行病学研究方法，以人群为对象，以 描述、分析和实验流行病学方法为基本手段，描 述恶性肿瘤的流行病学分布特征、寻找可疑的致 癌危险因素和肿瘤病因，探索和评价人群中早期 发现、预防和干预恶性肿瘤的方法，并与临床医 学相结合，研究和评价恶性肿瘤的治疗措施和效 果，为恶性肿瘤防治策略的制定提供了极其重要 的线索和依据。 Department of Epidemiology Public Health College of Harbin Medical University 阐明影响恶性肿瘤发病率或死亡率的地区间差 别和时间趋势的因素； 研究不同社区人群间恶性肿瘤发病率与人们生 活方式和环境间的相互关系； 比较患恶性肿瘤和不患恶性肿瘤人群之间可疑 危险因素的暴露情况，比较暴露和未暴露于可 疑危险因素人群恶性肿瘤发病情况； 恶性肿瘤流行病学的主要研究领域 Department of Epidemiology Public Health College of Harbin Medical University 对恶性肿瘤危险因素实施干预并评价干预效 果； 对恶性肿瘤发病机制和模型进行定性和定量 研究，阐明其发病机理 Department of Epidemiology Public Health College of Harbin Medical University 描述流行病学研究 (Descriptive epidemiologic study) To describe the difference in occurrence To describe the difference in occurrence of a particular cancer between different of a particular cancer between different groups (age, gender, race, country, a period groups (age, gender, race, country, a period of time for time trend) and to generate the of time for time trend) and to generate the hypothesis for increased/decreased for the hypothesis for increased/decreased for the specific tumor type.specific tumor type. Department of Epidemiology Public Health College of Harbin Medical University 建立健全的健康信息系统（health information system，HIS） 是完整描述恶性肿 瘤分布和流行趋势的最科学、有效的途径。世界 很多国家和地区，都将恶性肿瘤发病登记报告列 为HIS的一个重要组成部分。国际癌症研究中心 的汇报五大洲癌症发病率收录了肿瘤登记工 作开展较早的地区的肿瘤发病信息，目前已出版 第七卷。 Department of Epidemiology Public Health College of Harbin Medical University 2004年8月9日8：56 - 2004/07/15慢病中心修订中国成人慢病相关危险因素监测方案接近尾 声 为保证中国成人慢病相关危险因素监测的科学完善和经济高效，中国疾 控中心慢病中心在多轮专家征求意见和三轮现场试验的基础上，修改制定了 中国成人慢病相关危险因素监测方案(征求意见四稿)，并于2004年6月 10日起开始第四次大规模征求国内外相关领域专家的书面意见。此次征求 意见的专家，基本涵盖了目前世界卫生组织、美国、芬兰、英国以及国内从 事慢病监测、流行病与卫生统计学、疾病控制、人口学等相关领域的近四十 位权威学者。日前，已有二十多位专家反馈了意见，对中国成人慢病相关 危险因素监测方案（征求意见四稿）给予了充分的肯定，并提出了不少宝 贵意见。其余专家的意见正陆续反馈到慢病中心。 慢病中心监测组正根据专家反馈意见对监测方案进行修改，预计月中此 项工作即可完成，并将正式启动2004年监测工作。 Department of Epidemiology Public Health College of Harbin Medical University 专项的恶性肿瘤流行病学横断面研究，如 江苏启东、海门地区的肝癌、扬中地区的胃癌 和食管癌研究等，反映了这些消化系统癌症在 高发地区内不同时间、空间和人群间的分布， 为建立和检验消化系统癌症危险因素假设提供 了可靠的背景材料。 Department of Epidemiology Public Health College of Harbin Medical University 结合肿瘤登记工作开展的肿瘤危险 因素监测、肿瘤筛检、肿瘤的生态学研 究等，对探索肿瘤危险因素和病因，早 期发现、诊断、治疗肿瘤患者，有效防 治肿瘤具有重要意义。 Department of Epidemiology Public Health College of Harbin Medical University p病例对照研究是肿瘤病因学研究的常用方法 。其研究发现了大量的有价值的危险因素的 线索。 p队列研究包括前瞻性和回顾性队列研究。国 内外队列研究为进一步验证肿瘤的病因假设 发挥了巨大作用。 分析流行病学研究 (Analytic epidemiological study) Department of Epidemiology Public Health College of Harbin Medical University p山西子宫颈癌筛查研究队列数据库 中国医学科学院肿瘤研究所与美国克里夫兰 医学中心、美国NCI合作进行。于1998年启动 ，1999年在山西襄垣开始正式试验，共计 1997例妇女进入该队列。试验结果在法国获 “欧罗金”国际奖。2000年开始进行了更大 范围、共计九千人的筛查试验。对子宫颈癌 筛查手段进行了科学的评价，同时在病因流 行病学研究亦有重要意义。可为广大临床科 研究工作者借鉴参考。 Department of Epidemiology Public Health College of Harbin Medical University 不但有助于干预或预防肿瘤的发生， 而且能为肿瘤病因学研究提供有关危险因 素或病因的进一步佐证。 实验流行病学研究 (Experimental epidemiological study) Department of Epidemiology Public Health College of Harbin Medical University 河南林县食管癌化学干预试验数据库 八十年代开始，中国医学科学院肿瘤研究所与美国NCI合作 在河南林县开展了两个较大规模的研究项目，包括食管癌 营养干预试验、早诊早治及化学预防研究。营养干预试验 共干预人群共32902例，至今一直对干预人群进行跟踪随访 及定期普查；食管癌早诊早治及化学预防研究于1998年启 动，研究人群2213例，经内窥镜检查确定食管上皮病变， 对其中轻、中度不典型增生病人进行化学药物预防研究。 以上这些研究项目在国内外产生了很大的影响，不仅是食 管癌防治研究极其宝贵的资源，同时也给其它疾病的防治 提供经验 Department of Epidemiology Public Health College of Harbin Medical University 生物标志和肿瘤流行病学研究 随着细胞生物学、免疫学、毒理学分子 遗传学等生命科学的发展，越来越多的分析 测量技术拓展了分子标志物与传统流行病学 间的联系。 (Biomarker and tumor epidemiological study) Department of Epidemiology Public Health College of Harbin Medical University 内剂量（In doses ） 生物学效应剂量（Biological effective dose ） 临床前期生物学效果（Pre-clinical biological effects ） 易感性标志（Susceptibility marker ） 生物标志流行病学研究的方法学问题 生物标志种类 (Types of Biomarker) Department of Epidemiology Public Health College of Harbin Medical University Molecular Epidemiology Breaking Open the “Black Box”Breaking Open the “Black Box” Department of Epidemiology Public Health College of Harbin Medical University Molecular Epidemiology Internal Dose (Agent Metabolite) Biological Effective Dose (Adducts) Preclinical Biologic Effect (SCE oncogene TSG inactivation) ExposureExposure DiseaseDisease Department of Epidemiology Public Health College of Harbin Medical University 第二节 恶性肿瘤的流行特征 (恶性肿瘤的疾病负担) Epidemiological Characteristics of Malignancy Department of Epidemiology Public Health College of Harbin Medical University Measures of Cancer Frequency: Incidence pnumber of new cases occurring pcan be expressed as an absolute number of cases per year or as a rate per 100,000 persons per year. pincidence rate provides approximation to average risk of developing a cancer and is necessary to compare risk of disease between populations preduction in incidence is the appropriate statistics to use when considering impact of primary prevention strategies Department of Epidemiology Public Health College of Harbin Medical University Measures of Cancer Frequency: Mortality pnumber of deaths occurring pmortality rate is the number of deaths per 100,000 persons per year pmortality rates measure average risk of dying from a specific cancer pnumber of deaths is one measure of outcome or impact of cancer (product of incidence and fatality of a given cancer) pFatality, (1-survival), is probability that an individual with cancer will die from it and is generally assumed to be most severe sequelae of disease Department of Epidemiology Public Health College of Harbin Medical University pmortality rate sometimes used as convenient proxy measure of the risk of acquiring the disease (incidence) when comparing different groups, since it is more readily available pBUT we need to assume equal survival or fatality in the populations being compared pmost of time this assumption is not correct, so it is safer to use mortality as measure of outcome rather than occurrence Department of Epidemiology Public Health College of Harbin Medical University Measures of Cancer Frequency: Prevalence pNO agreed definition of “prevalence” of cancer pnumber of persons in a defined population alive at a given time who have had cancer diagnosed at some time in past poverall prevalence not useful for health care planning purposes because resource requirements for treating newly diagnosed patients are very different from those for supporting long-term survivors, especially since a large proportion of long-term survivors can be considered cured Department of Epidemiology Public Health College of Harbin Medical University Measures of Cancer Frequency: Prevalence ppartial prevalence limits number of patients to those diagnosed during fixed time in past and is more useful prevalence measure of cancer burden pprevalence for cases diagnosed within 1, 3, 5 years are likely to be of relevance to different stages of cancer therapy: initial treatment (1 year), clinical follow-up (3 years) and cure (5 years) ppatients still alive 5 years after diagnosis are considered “cured” since their death rates are similar to general population (some exceptions, like breast cancer) Department of Epidemiology Public Health College of Harbin Medical University Other Measurements: Survival psurvival time defined as time that elapsed between diagnosis and death pmost basic measure of patients survival is the observed survival p5-year observed survival is percentage of patients alive after 5 years of follow-up from date of diagnosis Department of Epidemiology Public Health College of Harbin Medical University Other Measurements: Relative Survival pdeaths from other competing causes will lower the observed survival rates and preclude comparison between groups where probability of death in the general population vary prelative survival rate can be calculated to avoid this problem prelative survival rate is observed survival rate in a patient group divided by expected survival of a comparable group in the general population with respect to age, sex, and calendar period of investigation Department of Epidemiology Public Health College of Harbin Medical University Other Measurements: PYLL pPotential Years of Life Lost (PYLL) measures how many years of normal life span are lost due to deaths from cancer ptakes into account both number of deaths and age at which death occurs pAge-weighting function used to increase the relative value of adults in productive ages, i.e., 1 year saved for someone at 20 years old is valued more than for a person aged 60 years pvarying weighting functions can be given according to quality of these life-years Department of Epidemiology Public Health College of Harbin Medical University 一、恶性肿瘤的分 布 (Distribution of cancer) （一）时间趋势 从世界范围来看，恶性肿瘤发病 率和死亡率逐年上升，且除宫颈癌和食管 癌外，所有恶性肿瘤都呈上升趋势。据世 界卫生组织专家预测，2020年全球人口80 亿，癌症新发病率将达2000万，死亡1200 万，癌症将是新世纪人类的第一杀手，并 成为全球最大的公共卫生问题。 Department of Epidemiology Public Health College of Harbin Medical University 过去十年间，全球癌症的发病及死亡增 长了约22%。2000年全球新发癌症病人1010 万，死亡620万。在各恶性肿瘤中，多数国 家肺癌的发病率和死亡率都在增长，肺癌以 成为全球最主要的癌症，年发病达120万， 死亡110万。 In the past 10 years, the prevelence and mortality of cancer increased to 22%.new cases were 10.1million in 2000,and 6.2 million died. Department of Epidemiology Public Health College of Harbin Medical University 全球癌症的发病顺位依次为肺癌、乳 腺癌、结直肠癌、胃癌。死亡顺位依次为 肺癌、胃癌、肝癌及结直肠癌。目前英美 等国的肺癌死亡率都以达到50/10万上下。 近10年来，由于全球控烟行动的开展，欧 美发达国家肺癌死亡率逐渐趋于平稳，在 年轻男性人群中，肺癌发病率更呈现出下 降趋势。 Department of Epidemiology Public Health College of Harbin Medical University 世界范围内，美国的癌症流行趋势 尤其受人瞩目。从1990始，美国癌症的 发病率和死亡率均呈下降趋势，在前10 位癌症中，8种下降或持平。其中男性肺 癌、前列腺癌和结直肠癌发病率和死亡 率均下降；女性乳腺癌死亡率也明显下 降，乳腺癌发病率的上升与早期筛检效 果有关。 Department of Epidemiology Public Health College of Harbin Medical University Department of Epidemiology Public Health College of Harbin Medical University The lung cancer epidemic - UK Department of Epidemiology Public Health College of Harbin Medical University The lung cancer epidemic - Canada Department of Epidemiology Public Health College of Harbin Medical University Department of Epidemiology Public Health College of Harbin Medical University Department of Epidemiology Public Health College of Harbin Medical University Department of Epidemiology Public Health College of Harbin Medical University Department of Epidemiology Public Health College of Harbin Medical University Department of Epidemiology Public Health College of Harbin Medical University Department of Epidemiology Public Health College of Harbin Medical University Tobacco Use in the US, 1900-1999 *Age-adjusted to 2000 US standard population. Source: Death rates: US Mortality Public Use Tapes, 1960-1999, US Mortality Volumes, 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2001. Cigarette consumption: Us Department of Agriculture, 1900-1999. Per capita cigarette consumption Male lung cancer death rate Female lung cancer death rate Department of Epidemiology Public Health College of Harbin Medical University Department of Epidemiology Public Health College of Harbin Medical University 按照全国肿瘤防治办公室对我国20年恶性肿 瘤率趋势研究，我国恶性肿瘤的调整死亡率由20 世纪70年代的84.58/10万上升为20世纪90年代的 94.36/10万，上升了11.56%。 上升的主要恶性肿瘤是肺癌、乳腺癌和白血 病，下降的主要恶性肿瘤是宫颈癌、鼻咽癌和食 管癌。其中肺癌上升了111.85%。 宫颈癌下降了69.00%。宫颈癌1980年曾列 世界女性恶性肿瘤第一位，但1985年后下降为第 二位，发病下降6%，其中主要是中国下降44%所致 。 我国主要恶性肿瘤流行状况 (Prevelence tendency in China) Department of Epidemiology Public Health College of Harbin Medical University Department of Epidemiology Public Health College of Harbin