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Presentation on theme: "EPI242 C ANCER E PIDEMIOLOGY S TAGES IN N EOPLASTIC D EVELOPMENT Zuo-Feng Zhang, MD, PhD Fall, 2009."— Presentation transcript:


2 C ONTENTS Carcinogenesis and stages for cancer development Molecular genetic alterations in cancer development Carcinogens Precursors

3 C ARCINOGENESIS The transformation of normal to neoplastic cells is caused by both endogenous and exogenous factors, including chemical and physical agents, viruses, activation of cancer-promoting genes, and inhibition of cancer-suppressing genes.

4 L ATENCY For infectious disease, the initial insult is the entrance of the infectious organism into the host and the latent period is the time during which the infectious organism multiplies and alters the host’s capacity for response, and manifested as the clinical apparent disease. For cancer, it refers a period of time between the initial etiologic insult and the clinical appearance of cancer, e.g., lack of parity (hormone, breast feeding) in Catholic nuns and high incidence of breast cancer; chimney sweeps (soot) as young boy and high incidence of cancer of the scrotum among adult males; and A-bomb survival and increased incidence of leukemia in Japan.



7 M ULTISTAGE C ARCINOGENESIS Two stages : Initiation and Promotion. The initial two stage theory base don the natural history of epidermal carcinogenesis in the mouse has lasted for many years. The limitation of the theory is that it does not emphasize the latent period of the development of other types of neoplasms.

8 S TAGES OF C ARCINOGENESIS Initiation is the first critical carcinogenic event and it is usually a reaction between a carcinogen and DNA. Two or more agents (chemicals, viruses, radiation) may act together as carcinogens. The process of initiation, the first stage in the natural history of neoplastic development, is permanent and irreversible.

9 S TAGES OF C ARCINOGENESIS Promotion is induced by a stimulator of cell proliferation and enhances the carcinogenic process. A promoter, not carcinogenic in itself, enhances other agents’ carcinogenicity. The progression in promotion process is reversibility and instability. The stage of promotion can be continually modulated by a variety of environmental alterations.


11 M ULTISTAGE C ARCINOGENESIS Three stages : Initiation, promotion, and progression. The two stage concept was modified and the original stage of promotion was then divided into two phases: promotion and progression. Progression phase is irreversible. Progression is a irreversible stage with demonstrated changes in the structure of the genome of the neoplastic cells. Such changes are directly related to increased growth rate, invasiveness, metastatic capability and biochemical changes of the neoplastic cell.


13 T UMOR G ROWTH In the normal proliferating tissue, a balance between cell renewal and cell death is strictly maintained In tumor growth, more cells are produced than die in a given time

14 H UMAN C ANCER -B ASED T WO - HIT M ODEL Two-hit model. Tumor suppressor gene such as RB gene. Knudson (1971) suggested that all types of retinoblastoma (RB) involve two separate mutations that are carried by all retinoblastoma tumor cells. In the case of sporadic retinoblastoma, he argued that both mutations occur somatically in the same retinal precursor cell. In heritable retonoblastoma, he suggested that one of the two mutations is already present at conception (germline mutation), and the second mutation occur as a somatic event (post conception).


16 H UMAN C OLON C ANCER M ULTIPLE S TAGE M ODEL Colon cancer model. The development of human cancer is a multistage process, involving a series of genetic molecular alterations.

17 E ARLY S TAGE VERSUS L ATE S TAGE “Early stage” versus “late stage” carcinogens in epidemiologic stages. If an agent is “early stage” carcinogen, both the increase in incidence beginning with and during exposure and decrease in incidence after cessation of exposure will be delayed. If an agent is a “late stage” carcinogen, responses both to starting and ceasing of exposure will be much more rapid. The terms, “early” and “late”, are used to correlate multistage models with epidemiologic results. Those may not necessary relate directly to the stages of initiation, promotion, and progression.



20 M OLECULAR G ENETIC OF C ANCER It is now recognized that the unregulated growth of cancer cells results from the sequential acquisition of somatic mutations in genes that control cell growth, differentiation, and apoptosis or that maintain the integrity of the genome Similar mutations may also be present in the germline of persons with hereditary predisposition to a variety of cancers


22 Mutations can be produced by environmental mutagens such as chemical carcinogens or radiation Mutations can also arise during normal cellular metabolism, particularly from the formation of activated oxygen species M OLECULAR G ENETIC OF C ANCER

23 DNA ENDOGENOUS DAMAGE AND R EPAIR Approximately 20,000 DNA damage lesions/cell/day 1 billion DNA damage lesions/human body/second Lindahl T, Quart Biol 2000,65,127-33

24 G ENETIC M UTATIONS AND T UMOR DEVELOPMENT Most of these mutations are of no consequence, because they either do not affect the function of the cell or are repaired by DNA repair genes, or are lost as a result of the death of the cell However, if the mutation involves genes that control growth or that protect the stability of the genome, it may give rise to a clone of cells that possess a growth advantage over their normal neighbors. Successive mutations in similar genes result in increasingly aberrant clones until a malignant phenotype eventually emerges.

25 C ELL T RANSFORMATION Malignant transformation involves somatic mutations that confer a set of common properties It is estimated that a minimum of 4-7 mutated genes are required for the transformation of a normal cell into a malignant phenotype

26 T RANSFORMED CELLS SHARE COMMON ATTRIBUTES Autonomous generation of mitogenic signals Insensitivity to exogenous antigrowth signal Resistance to apoptosis Limitless replicative potential (immortalization) Blocked differentiation Ability to sustain angiogenesis Capacity to invade surrounding tissues Potential to metastasize

27 O NCOGENES Oncogenes are altered version of normal genes, termed protooncogene, that regulate normal cell growth, differentiation, and survival Gain-of-function (dominant) mutations activate protooncogenes to become oncogenes and are positive effectors of the neoplastic phenotype

28 M ECHANISMS OF O NCOGENE A CTION Growth factors (IGF-1) Cell surface receptors Intracellular signal transduction pathways DNA-binding nuclear protein (transcription factors) Cell cycle proteins (cyclins and cyclin-dependent protein kinases) Inhibitors of apoptosis (bcl-2)

29 T UMOR S UPPRESSOR G ENES Tumor suppressor genes are normal genes whose products inhibit cellular proliferation. Loss-of – function (recessive) mutations inactivate the inhibitory activities of tumor suppressor genes, thereby permitting unregulated cell growth

30 T UMOR S UPPRESSOR G ENES A mutation that creates a deficiency of a normal gene product that exerts a negative regulatory control of cell growth and thereby suppresses tumor formation. Such genes encode negative transcriptional regulators of the cell cycle, signal-transduction molecules, and cell surface receptors.

31 T UMOR S UPPRESSOR G ENES Since both alleles of such tumor suppressor genes (“gatekeeper” genes) must be inactivated to produce the deficit that allows the development of a tuor, it is inferred that normal suppressor gene is dominant. The loss of heterozygosity in a tumor suppressor gene by deletion or somatic mutation of the remaining normal allele predisposes to tumor development

32 E XAMPLE : R ETINOBLASTOMA GENE (RB) AND P53 GENE The function of RB is the most critical checkpoint in the cell cycle, the inactivating mutations in RB permits unregulated cell proliferation. The mutations of p53 seem to be the most common genetic changes in human cancer.

33 E XAMPLE : R ETINOBLASTOMA GENE (RB) AND P53 GENE The p53 molecule is a negative regulator of cell division. In response to DNA damage, oncogenetic activation of other proteins, or other stresses, p53 levels rise and prevent cells from entering S phase of the cell cycle, thereby allowing time for DNA repair to take place. Inactivating mutations of p53 allow cells with damaged DNA to progress through the cell cycle.



36 DNA methylation—The covalent addition of a methyl group to the 5 th position of cytosine within CpG dinucleotides, which are frequently located in the promoter regions of genes. Methylation can also occur in other parts of genes. DNA methylation play a key role in a number processes, including DNA repair, genome stability, and regulation of chromatin structure. DNA methylation—The covalent addition of a methyl group to the 5 th position of cytosine within CpG dinucleotides, which are frequently located in the promoter regions of genes. Methylation can also occur in other parts of genes. DNA methylation play a key role in a number processes, including DNA repair, genome stability, and regulation of chromatin structure. (Laird PW. Molecular Medicine Today. 1997:223-229)

37 DNA methylation and Cancer— tumor suppressor gene (Laird PW..Molecular Medicine Today. 1997:223-229)

38 C ARCINOGENS An agent that can cause cancer. The International Agency for Research on Cancer (IARC) classifies carcinogens as follows: 1) Sufficient evidence. A positive causal relationship has been established between exposure and occurrence of cancer.

39 C ARCINOGENS 2) Limited evidence. A positive causal association has been observed between exposure to the agent, for which a causal interpretation is credible, but chance, bias, confounding cannot be rolled out.

40 C ARCINOGENS 3) Inadequate evidence. Available studies are of insufficient quality, consistency or statistical power to permit a conclusion regarding the presence or absence of a causal relationship.

41 C ARCINOGENS 4) Evidence suggesting lack of carcinogenicity. Several adequate studies covering the full range of doses to which humans are known to be exposed are mutually consistent in not showing a positive association between exposure to the agent and any studied cancer at any level of exposure.

42 O VERALL EVALUATION OF CARCINOGEN Taking all the evidence into account, the agent is assigned to one of the following categories: Group 1. The agent is carcinogenic to humans. Group 2. 2A. The evidence for human carcinogenicity is almost sufficient (probably carcinogenic). 2B. There are no human data but there is experimental evidence of carcinogenicity (possibly carcinogenic). Group 3. The agent is not classifiable as to its human carcinogenicity. Group 4. The agent is probably not carcinogenic to humans.




46 C ARCINOGENS IN T OBACCO S MOKE (According to International Agency for Research on Cancer, unless otherwise noted)

47 G ROUP 1: C ARCINOGENIC TO H UMANS Tobacco Smoking Tobacco Products, Smokeless 4-Aminobiphenyl (4-ABP) Benzene Cadmium Chromium 2-Naphthylamine (2-NA) Nickel Polonium-210 (Radon) Vinyl Chloride

48 G ROUP 2A: P ROBABLY C ARCINOGENIC TO H UMANS Acrylonitrile Benzo[a]pyrene Benzo[a]anthracene 1,3-Butadiene Dibenz(a,h)anthracene Formaldehyde N-Nitrosodiethylamine N-Nitrosodimethylamine

49 G ROUP 2B: P OSSIBLY C ARCINOGENIC TO H UMANS Acetaldehyde Benzo[b]fluoranthene Benzo[j]fluoranthene Benzo[k] fluoranthene Dibenz[a,h]acridine Dibenz[a,j]acridine 7H-Dibenz[c,g]carbazole

50 G ROUP 2B: P OSSIBLY C ARCINOGENIC TO H UMANS Dibenzo(a,i)pyrene Dibenzo(a,l)pyrene 1,1-Dimethylhydrazine Hydrazine Indeno[1,2,3-cd]pyrene Lead 5-methylchrysene

51 G ROUP 2B: P OSSIBLY C ARCINOGENIC TO H UMANS 4-(Methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK) 2-Nitropopane N -Nitrosodiethanolamine N -Nitrosomethylethylamine N -Nitrosomorpholine N -Nitrosonornicotine (NNN) N -Nitrosopyrrolidine

52 G ROUP 2B: P OSSIBLY C ARCINOGENIC TO H UMANS Quinoline ortho-Toluidine Urethane (Ethyl Carbamate)

53 G ROUP 3: U NCLASSIFIABLE AS TO C ARCINOGENICITY TO H UMANS (L IMITED E VIDENCE ) Chrysene Crotonaldehyde N -Nitrosoanabasine (NAB) N -Nitrosoanatabine (NAT)

54 If DNA damage not repaired DNA damage repaired If loose cell cycle control Defected DNA repair gene G S G2 M P53 Cyclin D1 P16 Environmental Carcinogens / Procarcinogens Exposures PAHs, Xenobiotics, Arene, Alkine, etc Active carcinogens Detoxified carcinogens DNA Damage Normal cell Carcinogenesis Programmed cell death Tobacco consumption Occupational Exposures Environmental Exposure CYP1A1 GSTP1 mEH NQO1 XRCC1 GSTM1 2-1. Background: Theoretical model of gene-gene/environmental interaction pathway Ile 105 Val  Ala 114 Val  Tyr 113 His  His 139 Arg  Tyr 113 His  His 139 Arg  Pro 187 Ser  MspI Ile 462 Val  Arg 194 Trp, Arg 399 Gln, Arg 280 His  Null  Ala 146 Thr Arg 72 Pro  G 870 A 

55 C HEMICAL / ENVIRONMENTAL CARCINOGENS Smoking and lung cancer Sun exposure and squamous cell carcinoma of skin Asbestos exposure and lung cancer Smoke food risk with nitrosamines and adenocarcinoma of the stomach Alcohol drinking and squamous cell carcinoma of esophagus Aflatoxin B1 and liver cancer Low fiber diet and adenocarcinoma of colon


57 R ADIATION Exposure to ultraviolet radiation (in the form of sunlight) and squamous cell carcinoma of skin Ionizing radiation is related to skin cancer and leukemia in radiologist


59 V IRAL FACTORS HPV (human papilloma virus) and Cervix cancer EBV(Epstein-Barr virus) and Nasopharyngeal cancer, Burkitt’s lymphoma HBV (hepatitis B virus) and hepatocellular carcinoma HIV (human immunodeficiency virus) and Kaposi’s sarcoma


61 P RECURSORS Is a condition which be associated with the development of cancer (Stout, 1932) Visible steps in a dynamic process of neoplasia that may or may not undergo progression to a more advanced stage of neoplasia (Foulds, 1958) All morphologic lesions on the pathway from normal tissue to cancer, up to but not including invasive cancer

62 P RECURSORS Two groups: less advanced lesions, which do not include abnormal clones more advanced lesions or dysplasia, which include abnormal clones and are considered dangerous if untreated

63 S IGNIFICANCE Elucidation of the etiology of precursors provides insight into etiology of the corresponding cancer Identification of etiology of precursors may provide opportunity for primary prevention for both precursors and invasive cancer If precursors are defined, they can provide targets for screening and early detection and chemoprevention of these at an increased risk of cancer They can provide functional inside into the nature of carcinogenesis


65 O RAL L ESIONS Incidence rates of leukoplakia (/1000) are 3.3-5.5 for men and 1.9-3.6 for women. 11-43% of individuals with leukoplakia may have histologically defiend dysplasia. Incidence rates for erythroplakis have not clearly defined yet. More than two thirds of cases with histologically defined dysplasia or carcinoma Incidence rates for oral submucous fibrosis (OSF) (/1,000) are 8-21 in men and 29-46 in women

66 Oral Leukoplakia Oral submucous fibrosis Erythroplakia Oral Lesions 2. Invasive Head & Neck Cancer 3. Second Primary Cancers following a first primary oral cancer Esophageal CancerOral CancerLung Cancer




70 R ESEARCH O PPORTUNITIES FOR P RECURSOR Precursor cellular changes hold the clue to an understanding of the mechanisms of multistep carcinogenesis Abnormal proteins formed by precursor lesions can help in the exploration of the neoplastic process as well as in the identification of high risk individuals The precursor lesions can be employed to study genetic susceptibility and environmental exposure.

71 R ESEARCH O PPORTUNITIES FOR P RECURSOR Study of progression of precursor lesions can help to determine if the etiological factors under study influence the initiation or the promotion of the neoplastic process Precursor lesions have a shorter latency period to develop as cancer. Study of precursor lesions will give researcher shorter follow-up time. The identification of precursor lesions changes offers hope of inducing the regression of lesions. This is explored in chemoprevention trials.


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