学习遗传cancer genetics单击此处编辑母版标题

1、Chapter 14上海交通大学医学院Shanghai Jiao Tong University School of MedicineLei Huang, Ph.D., Prof.Department of P梅艳芳梅艳芳沈殿霞沈殿霞陈晓旭陈晓旭罗京罗京In the United State, more than 1 million people are diagnosed with cancer each yearIn China, more than 2 million people are diagnosed with cancer each year, 1.5 million die.

2、 N ENGL J MED 353：11，2005 Strikes more than one third of the population（30%）.Accounts for more than 20% of all deaths.Responsible for more than 10% of the total cost of medical care in developed countries. Cancer Is Named for the Site in the Body Where It First Develops Carcinoma (癌癌)(Epithelial tis

3、sue) Sacoma (肉瘤肉瘤)(Mesenchymal tissue) Lymphoma(Lymphoid)Leukimia(Hematopoietic) OtherHematopoietic and lymphoid malignancies(造血和淋巴系统恶性肿瘤造血和淋巴系统恶性肿瘤)MelanomasALLAMLInvasionMetastasisColon carcinomas to liverUncontrolled division肿瘤的概念肿瘤的概念1. 由一群生长失去正常调控生长失去正常调控的细胞形成的赘生物（neoplasm）。上皮细胞来源的恶性肿瘤又称为癌症（Can

4、cer） ；间叶细胞来源的称为肉瘤（Sarcoma）。2. 通常由一个累积多种基因突变累积多种基因突变的体细胞增殖而来;3. 浸润生长或远端转移浸润生长或远端转移, 导致周围或远端组织损伤和器官衰竭。I. Cancer is a genetic disorder. Why?II. Genetic basis of cancer. What ?III. The hypothesis of carcinogenesis. How?1. Inherited cancer (遗传性肿瘤遗传性肿瘤)1.1 Single-gene inherited-Retinoblastoma1.2 Li-Fraume

5、ni Syndrome -Cancer familyGreen-breast cancer; Yellow- glioblastoma; Purple- lukemia; Blue- lung cancer; Orange-pancreatic carcinoma; Red- sarcoma; Brown-Wilms tumor1.3 Multifactorial inherited cancerCancer cluster: Large number of cases in restricted areaBreast cancer- America， 117.7/10000 China，24

6、/10000江苏盐城市盐江苏盐城市盐都区龙冈镇新都区龙冈镇新岗村岗村: 在最近的七八年，新岗村初步调查有57个癌症患者，死亡年龄都在50岁到60岁之间。河北涉县（固河北涉县（固新村等至少新村等至少6 6、7 7个村庄）：个村庄）：上世纪80年代的统计数字显示，该地域的食管癌、胃癌发病率为全国平均发病率的20多倍。Both of genetic factor and environment factor contribute to tumorigenesis.Cancer is, in essence, a genetic disease caused by germ-line or somat

7、ic cells gene disorder.- 90% of cancer genes show somatic mutations in cancer, 20% show germline mutations and 10% show both. (Michael R. Stratton et al . Nat Rev Cancer. 2004)Carcinogens and certain behaviors increase rate of mutations and cancer riskCancer Is a Genetic DisorderGenetic basis of can

8、cer1. Chromosomal aberrations非整倍体（aneuploid）：X/23整数；超二倍体(hyperdiploid)：比46多一条或几条染色体；亚二倍体(hypodiploid)：比46少一条或几条染色体；亚三倍体(hypotriploid)：比69少一条或几条染色体；亚四倍体(hypotetraploid) ：比92少一条或几条染色体；多倍体（polyploid）：染色体数目在三倍体以上者。肿瘤由单克隆起源，但在生长过程中演变为多克隆，出现异质性（heterogeneity)。其中占主导数目的克隆称为肿瘤的干系（stem line）;占非主导数目的克隆称为旁系（sid

9、e line）;干系肿瘤细胞的染色体数目称为众数（modal number）。Boveris theory (肿瘤染色体理论肿瘤染色体理论)1914年，年，Theodor Boveri在恶性肿瘤在恶性肿瘤细胞中发现染色体异常，提出肿瘤的细胞中发现染色体异常，提出肿瘤的染色体理论染色体理论 肿瘤起源于一个染色体异常的细胞肿瘤起源于一个染色体异常的细胞 染色体畸变是引起正常细胞恶性转化染色体畸变是引起正常细胞恶性转化的主要原因的主要原因 1862-19151960，discover by Nowell;95% of cases of CML1973，identify by Rowley t(9;2

10、2)(q34;q11);Chronic Myelocytic Leukemia (CML) Philadephia chromosomeMarker chromosome(标记标记染色染色体体)： 在在肿肿瘤中瘤中稳稳定定遗传遗传的、具有特的、具有特殊殊结构结构的畸的畸变变染色体。染色体。2. Oncogene (癌基因癌基因)(1) Discovery of oncogene Peyton Rous(1910)：Rous Sacoma Virus (RSV) Genetic basis of cancerPeyton Rous(1879-1970), Nobel Prize in Medic

11、ine and Physiology in 19661970, Howard Temin & David Baltimore proved that RSV was a Retro Virus (1975 Nobel Prize)1975年，年，J. Michael Bishop & Harold Varmus (UCSF) found the first pro-oncogene-SrcTd: transformation-defective mutantSrc is not a gene of avian leukosis virusCapture of src by avian leuk

12、osis virusThe Biology of Cancer, Robert A. WeinbergProto-oncogene: A normal cellular gene that, upon alteration by DNA damage agents or viral genomes, can acquire the ability to function as an oncogene.Oncogene：A cancer-inducing gene; A gene that can transform cells Concept of oncogeneGenetic basis

13、of cancer 原癌基因原癌基因(pro-oncogene):一种正常的细胞内基因，当受到DNA损伤或病毒基因组的诱导时能变成癌基因。即没有激活的癌基因。 癌基因癌基因(oncogene):能将正常细胞转化为肿瘤细胞的基因。癌基因表达的蛋白质称癌蛋白 (oncoprotein)。 So far, 384 cancer genes have been reported, more than 2% of all the genes in the human genome.Genetic basis of cancerMichael R. Stratton et al . Nat Rev Can

14、cer. 2004 & 2010Viral oncogene and cellular oncogene v-onc c-onc 结构 无内含子 有内含子 功能 非病毒的生长 细胞正常生长分化 繁殖所必需 绝对必需 有急性致癌作用 无致癌作用 联系 病毒癌基因来自细胞癌基因Genetic basis of cancerGenetic basis of cancer(2) Functions of the proto-oncogene proteinsClassification and nomenclature of oncogene- According to the difference

15、of production and function, oncogenes can be divided into 5 families ： Growth factor(生长因子) Receptors (生长因子受体) Signaling cascades（信号转导因子） Transcription factor（转录因子） Other（ Apoptotic machinery细胞凋亡因子） Genetic basis of cancer(1) Point mutation（基因突变）3. Activation of proto-oncogeneGenetic basis of cancerA

16、ctivatedc-onccancerCodonMutationAmino acidHRAS1Bladder cancerBreast cancerLung cancer121261GGCGTCGGCGACCAGCTGglyvalglyaspglnleuKRAS2Lung cancerColon cancer1212GGTTGTGGTGTTglycysglyvalNRASAML12GGCGACglyaspNeuroblastoma61CAGAAGglnlysPoint mutation of Ras can be found in 30% of lung cancer, 50% of colo

17、n cancer, 90% of pancreatic cancer . From Harvey murine Sarcoma Virus From Kister murine Sarcoma Virus 从人神经胚胎瘤的细胞中发现 The Ras signaling cycleGEF:guanine nucleotide exchange factor GAP:GTPase-activating proteinsGenetic basis of cancerHomogeneously staining region(2) Gene amplificationhomogeneously sta

18、ining region(匀染区)Double minute of Her2/Neu in mouse breast cancer cellGene amplificationDouble minute chromosome, DMs (双双微体微体)Gene amplificationCancer Cellular oncogene Amplification Small cell lung cancer MYC GL12（NMYC） LMYC 80-fold 50-fold 20-fold Neuroblstoma GL12（NMYC） 250-fold Glioblastoma EGFR

19、（ERBB1） 50-fold Breast cancer-fold ERBB2 30-fold Live cancer HRAS 30-60 (3) Transposition activation （转位激活（转位激活 ）A. Change the quantity of proteinGenetic basis of cancerBurkitt lymphomaB. Change the quality of productChronic myelogenous leukemia, CMLGleevec3. Tumor suppressor gene ( TSG,肿瘤抑肿瘤抑制基因或抑癌

20、基因制基因或抑癌基因) Harris(1971) cell fusion experiment Mouse tumor cell + normal cell= normal cell HeLa + normal fibroblast = normal cell HeLa+ minicell with chromosome 7=normal 肿瘤抑制基因：一类抑制肿瘤发生的基因；或一类在受精卵或体细胞中部分或完全失活时，将导致肿瘤发生的基因。Genetic basis of cancer(1) RB and Retinoblastoma （视网膜母细胞瘤（视网膜母细胞瘤) 1/20000 in

21、children Unilateral or bilateral About 40% are inherited, behavior of AD, usually bilateral ，2 year RB within 13q14.1, mRNA 7.5kb, protein 110kD Regulates cell cycleGenetic basis of cancer 30% large fragment deletion Mis-spliced Point mutation Small deletion in promoter DNA Tumor Virus、SV40 binds to

22、 RbRB and Retinoblastoma(2) p53 and cancer family Genetic basis of cancerClinic features：Association with every forms of cancer.(人体各部位均可发生)The incidence is high among familial members.(家族中发病率高)The tumor tends to occur at an earlier average age. (发病年龄早)AD inheritance. ( AD遗传)P53-activating signals an

23、d p53s downstream effectsTP53 gene P53 gene within 17p13.1 with 20kb of full length gDNA, harboring 11exons; coding 53 KD of protein; Regulates cell G1 arrest and induces apoptosis, responding to stress; Inactive p53: Mutation of p53, 95.1% in DNA binding domain; Negative regulation of MDM2/MDMX Blo

24、ck by oncoprotein, e.g. SV40 large T ,E1A.Dominant-negative（显显性性负负效效应应）:referring to a mutant allele of a gene that, when co-expressed with the wild type allele of the gene, is able to interfere with the functioning of the latter.(3)APC and familial adnomatous polyposis, FAP (家族性腺瘤样息肉) 呈AD遗传 发病率为1/8

25、000， 结直肠广泛密集分布腺瘤性息肉，在西方，1%恶变为腺癌。 基因APC定位于5q21，其产物参与细胞连接、细胞周期调控及转录调控。Genetic basis of cancerFAP family AR致死性遗传病，发病致死性遗传病，发病率为率为1/25万；万； 对紫外线敏感；对紫外线敏感； 皮肤易发生色素沉着、皮肤易发生色素沉着、红斑、水疱；红斑、水疱； 常恶化为鳞状上皮癌、常恶化为鳞状上皮癌、黑色素瘤、皮肤基底细黑色素瘤、皮肤基底细胞癌及白血病；胞癌及白血病； 肿瘤发生比正常人群高肿瘤发生比正常人群高1000倍；倍；(4) 着色性干皮病着色性干皮病(XP)核核苷苷酸切除修酸切除修复复

26、系系统统（NER）NER由一系列酶组成由一系列酶组成(XPA-XPG)，任何一种酶突变都，任何一种酶突变都可诱发疾病。可诱发疾病。 XPA-9q22.3, XPC-3q25。(5)BRCA1基因与乳腺癌基因与乳腺癌 BRCA1 (Breast cancer predisposition gene 1), 17q21, cDNA 7.8 kb, 120kD 家系乳腺癌易感性为40-50% ； 卵巢癌发病风险为40-50% BRCA2, 13q12-13 10%卵巢癌发病风险 6%男性乳腺癌发病风险Genetic basis of cancerBrca2 mutant cellTumor supp

27、ressor geneCaretaker geneTP53APCRB BRCA1XP原癌基因与肿瘤抑制基因的比较原癌基因与肿瘤抑制基因的比较 表表 12-812-8 原癌基因核肿瘤抑制基因的比较原癌基因核肿瘤抑制基因的比较特点特点原癌基因原癌基因肿瘤抑制基因肿瘤抑制基因基因属性基因属性正常生长和增殖必需正常生长和增殖必需增殖负调控，分化必需增殖负调控，分化必需遗传损伤遗传损伤点突变，基因融合，扩增点突变，基因融合，扩增点突变，缺失、杂合性丢失点突变，缺失、杂合性丢失致癌方式致癌方式显性突变，杂合子致癌显性突变，杂合子致癌隐性突变纯合子或半合子致癌隐性突变纯合子或半合子致癌遗传方式遗传方式体细胞

28、突变，不遗传体细胞突变，不遗传体细胞或种质细胞突变可遗传体细胞或种质细胞突变可遗传多见癌肿多见癌肿白血病，淋巴瘤白血病，淋巴瘤实体瘤实体瘤Genetic basis of cancerPredict outcome by gene profiling 染色体畸变染色体畸变 标记染色体标记染色体 癌基因癌基因 癌基因的发现、定义、分类、激活方式（突变、癌基因的发现、定义、分类、激活方式（突变、扩增、染色体重排）及致病机制；病毒癌基因与细扩增、染色体重排）及致病机制；病毒癌基因与细胞癌基因二者的区别及相互关系胞癌基因二者的区别及相互关系 肿瘤抑制基因肿瘤抑制基因 定义及致病机理；定义及致病机理；

29、RB（LOH）；）； p53(显性负效显性负效应应)；APC；BRCA1/BRCA2；XP；与癌基因的区；与癌基因的区别与联系；别与联系；Genetic basis of cancer1. The monoclonal nature of cancer (One)2. Knudsons two-hit hypothesis (Two)3. Multi-Step Tumorigenesis (Multiple)The hypothesis of carcinogenesis1. The monoclonal nature of cancer (One)-The tumor arose from

30、a single cell. 肿瘤组织是单细胞起源的，即肿瘤的单克隆性(monoclonality)。肿瘤细胞是由单个突变的前体细胞增殖而来。The hypothesis of carcinogenesis(1) Evidence from X chromosomeThe monoclonal nature of cancer（2） Proof from immunoglobulinThe monoclonal nature of cancer（3） In all of the malignant cells of a CML patient harbor a balanced translocation t(9;22)(q34;q11). The monoclonal nature of cancer2. Knudsons two-hit hypothesis (Two) 无论是遗传性肿瘤还是散发性肿瘤的发生均需无论是遗传性肿瘤还是散发性肿瘤的发生均需二次或二次以上的突变。二次或二次以上的突变。 遗传性肿瘤：第一次突变发生在生殖细胞，或由遗传性肿瘤：第一次突变发生在