大一下课件chapter14cancer 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 year.In China, more than 2 million people are diagnosed with cancer each year, 1.5 million die

2、.Strikes more than one third of the population（30%）.Accounts for more than 20% of all deaths.In developed countries, is responsible for more than 10% of the total cost of medical care. Cancer Is Named for the Site in the Body Where It First Develops Carcinoma (癌癌)(Epithelial cells) Sacoma (肉瘤肉瘤)(Mes

3、enchymal cells) Lymphoma(Lymphoid cells) Leukemia(Hematopoietic cells) 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 divisionComplex disease, affects many different cells and tissuesCharacterized by uncontro

4、lled cell divisionMalignant cells spread, or metastasize, to other sites within the bodyUnchecked growth may result in deathNot all tumors are cancerous, benign tumors, increase in size, but do not metastasizeI. Cancer is a genetic disorder. Why?II. Genetic basis of cancer. What ?III. The hypothesis

5、 of carcinogenesis. How?1. Inherited cancer1.1 Single-gene inherited-Retinoblastoma1.2 Li-Fraumeni Syndrome -Cancer familyGreen-breast cancer; Yellow- glioblastoma; Purple- lukemia; Blue- lung cancer; Orange-pancreatic carcinoma; Red- sarcoma; Brown-Wilms tumor1.3 Multifactorial inherited cancerCanc

6、er cluster: Large number of cases in restricted areaBreast cancer- America， 117.7/10000 China，24/10000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 c

7、ontribute to tumorigenesis.Cancer is, in essence, a genetic disease caused by germ-line or somatic 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 beha

8、viors increase rate of mutations and cancer riskCancer Is a Genetic Disorder1. Chromosomal aberrations1960，discover by Nowell95% of cases of CML1973，identify by Rowley t(9;22)(q34;q11);Why do they spend 13 years ?G band technique was established in 1971.Chronic Myelocytic Leukemia (CML) Philadephia

9、chromosome2. Oncogene2.1 Discovery of oncogene Peyton Rous(1910)：Rous Sacoma Virus (RSV) Peyton Rous(1879-1970), Nobel Prize in Medicine and Physiology in 1966In 1970, Howard Temin & David Baltimore proved that RSV was a Retro Virus (Nobel Prize in 1975 ) In 1975，J. Michael Bishop & Harold V

10、armus (UCSF) found the first pro-oncogene Src Discovery of oncogeneThe 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 t

11、hat can transform cells 2.2 Concept of oncogeneGenetic basis of cancerViral oncogene and cellular oncogene v-onc c-onc Intron no yes Function not necessary necessary for development Relationship v-onc is derived from c-oncGenetic basis of cancer2.3 Functions of the proto-oncogene proteins2.4 Classif

12、ication and nomenclature of oncogene According to the difference of production and function, oncogenes can be divided into 5familiesGrowth factorReceptors Signaling cascadesTranscription factorOther（apoptotic machinery） Detail please find in Table 11-1 on page 1973.1 Point mutation3. Activation of p

13、roto-oncogeneActivatedc-onccancerCodonMutationAmino acidHRAS1Bladder cancerBreast cancerLung cancer121261GGCGTCGGCGACCAGCTGglyvalglyaspglnleuKRAS2Lung cancerColon cancer1212GGTTGTGGTGTTglycysglyvalNRASAML12GGCGACglyaspNeuroblastoma61CAGAAGglnlysPoint mutation of Ras can be found in 30% of lung cance

14、r, 50% of colon cancer, 90% of pancreatic cancer . From Harvey murine Sarcoma Virus From Kister murine Sarcoma Virus From human Nervous Embryonal Tumor cell The Ras signaling cycleGEF: guanine nucleotide exchange factor GAP: GTPase-activating proteins Homogeneously staining region3.2 Gene amplificat

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

16、Glioblastoma EGFR（ERBB1） 50-fold Breast cancer-fold ERBB2 30-fold Live cancer HRAS 30-60 Cancer Cellular oncogene Amplification Small cell lung cancer MYC GL12（NMYC） LMYC 80-fold 50-fold 20-fold Neuroblastoma GL12（NMYC） 250-fold Glioblastoma EGFR（ERBB1） 50-fold Breast cancer-fold ERBB2 30-fold Live

17、cancer HRAS 30-60 3.3 Transposition activationA. Change the quantity of proteinGenetic basis of cancerBurkitt lymphomaB. Change the quality of productChronic myelogenous leukemia, CMLGleevec 导论 p397Genetic basis of cancerHarris(1971) cell fusion experimentMouse tumor cell + normal cell= normal cell

18、HeLa + normal fibroblast = normal cellHeLa+ minicell with chromosome 7=normal3. Tumor suppressor gene ( TSG,肿瘤抑制基因或抑癌基因)1) A gene whose partial or complete inactivation, occurring in either the germ line or the genome of a somatic cell, leads to an increased likelihood of cancer development. 2) Such

19、 a gene that is responsible for constraining cell proliferation.3.1 RB and Retinoblastoma （视网膜母细胞瘤（视网膜母细胞瘤)Clinic features：1/20000 in childrenUnilateral or bilateralAbout 40% are inherited, behavior of AD, usually bilateral ，2 yearRb within 13q14.1, mRNA 7.5kb, protein 110kDRegulates cell cycle 30%

20、large fragment deletion Mis-spliced Point mutation Small deletion in promoter DNA Tumor Virus、SV40 binds to RbInactive of Rb3.2 p53 and cancer family Clinic features：1.Association with every forms of cancer2.The incidence is high among familial members3.The tumor tends to occur at an earlier average

21、 age4.AD inheritance. P53-activating signals and p53s downstream effectsTP53 geneP53 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 in 100% of cancer:1. Mutation of p53,95

22、.1% in DNA binding domain;2. Negative regulation of MDM2/MDMX;3. Block by oncoprotein, e.g. SV40 large T ,E1A.3.3 NER (nucleotide excision repair) and Xeroderma pigmentosum (XP, 着色性干皮病着色性干皮病)Xeroderma pigmentosumExtreme sensitivity to UV radiation, induces severe and extensive lesions in all areas o

23、f sun-exposed skin; AR inheritance, 1/25,000. Show dry, parchment-like skin and many freckles;1000-fold increased risk of skin cancer compared with the general population and about 100,000-fold increased risk of squamous cell carcinoma of the tip of the tongue;About 18% of the patients have increase

24、d risk of other diseases, such as neurological problems.NER complex include eight XP-associated genes, seven of them named XPA through XPG, the eighth named XPV. Anyone of XP-gene mutation could induce XP. XPA-9q22.3 and XPC-3q25 has higher mutation rate.3.4 BRCAs and Breast cancer Most common form

25、of cancer in U.S. woman, 40,000 die, 178,000 new cases per year, 15% families, multiple cases of breast cancerMutations in BRCA1 (Breast cancer predisposition gene 1), and BRCA2 predispose women to breast cancer and ovarian cancer.Initial studies showed a greater than 80% risk of breast cancer by th

26、e age of 70 years in women heterozygous for BRCA1 or BRCA2 mutations. Discovery in 1990, 17q21, cDNA 7.8 kb, 120kDDominantly inherited, carry one mutant copy gene, develop breast cancer if other copy mutates - 82%: Second mutation = breast cancer - 44%: Second mutation = ovarian cancerBRCA1Angelina

27、Jolie undergoes double mastectomy BRCA2Discovered in 1995, chromosome 13q12-13When mutated, causes breast cancer susceptibilityRare in general population, 1% Some populations much higher Ashkenazi Jews combined frequency of BRCA1 and BRCA2 is 2.5% Ashkenazi Jews and black males have higher rates of

28、breast cancerBrca2 mutant cellEnzymes for mismatch or excision repairFail to repair DNA mutationsRepair DNA mutationsDNA repair gene mutationCheckpoint moleculesFails to suppress divisionSuppresses cell divisionTumor suppressor geneGrowth factorsPromotes division - abnormal time or cell typePromotes

29、 divisionOncogeneGenes work together to maintain homeostasis Predict outcome by gene profiling 1. Chromosomal aberrations 2. Oncogene Discovery, concept, category, activation (mutation, amplification, transposition), viral oncogene and cellular oncogene3. Tumor suppressor geneConcept, Rb, p53；XPs, B

30、RCA1/BRCA2；inactiveGenetic basis of cancer1. The monoclonal nature of cancer (One)2. Knudsons two-hit hypothesis (Two)3. Multi-Step Tumorigenesis (Multiple)1. The monoclonal nature of cancer (One)The vast majority of human tumors are monoclonal growths descended from single progenitor cells that too

31、k the first small steps to becoming cancerous.Since many of the genetic markers in these descendant cells will be present only in specific subpopulations of cells within the tumor mass.The hypothesis of carcinogenesis1.1 Evidence from X chromosomeThe hypothesis of carcinogenesis1.2 Proof from immuno

32、globulinThe hypothesis of carcinogenesisIn normal plasma, the immunoglobulin (Ig) molecules (i.e., antibodies) migrate as heterogeneity, which indicates a polyclonal population of plasma cells in antibody production.In the disease of multiple myeloma, this heterogeneous population of Ig molecules is

33、 replaced by a single antibody species that is produced by a single clonal population of antibody-secreting tumor cells.1.3 Proof from Ph chromosome The hypothesis of carcinogenesisIn all of the malignant cells of a CML patient harbor a balanced translocation t(9;22)(q34;q11). 2. Knudsons two-hit hy

34、pothesis (Two) The hypothesis of carcinogenesisDeveloping second and subsequently occurring tumor in a variety of organ sites. Inherited（BiL） Sporadic（UniL） DeletedSomatic Rb/rb Rb/Rb Rb/-Tumor rb/rb or rb/- rb/rb or rb/- rb/- or -/-Elimination of wild-type Rb gene copiesLoss of heterozygosity ( LOH

35、) in RetinoblastomaKnudsons two-hit hypothesisMultiple hits to DNA were necessary to cause cancer. In the children with inherited retinoblastoma, the first insult was inherited in the DNA, and any second insult would rapidly lead to cancer. In non-inherited retinoblastoma, two hits had to take place before a tumor could develop, explaining the age difference.3. Multi-Step Tumorigenesis (Multiple) The hypothesis of carcinoge