Presentation on theme: "Etiology and Risk Factor of Cancer"— Presentation transcript:
1 Etiology and Risk Factor of Cancer Noorwati SutandyoDharmais Cancer Center /Division of Hematology-Medical OncologyDept Internal MedicineUniversity of Indonesia School of MedicineInternational Class May 2013
2 CANCER Incidence of cancer is high and going higher every year Globocan: 12.7 million new cancer cases 2008Nearly double to 21.4 million cases by 2030Cancer causes 1 in 8 deaths worldwide becoming a global pandemicCancer is killing more people in the developing world than HIV/AIDS, tuberculosis, and malaria combined
3 Jakarta Minimum Cancer Incidence (Coverage 70% ) 79 Hospitals. 2 Private Clinics, 90 Pathology Laboratories,44 Municipals Primary health Care (as a coordinator of 301 Primary Health Care in District area).3
5 Cancer Definition Cancer is abnormal growth of cells. Cancer cells will growth fast even with limited of space and nutrition.Heterogenous: more than 100 different types of cancerSome are familial : 5-10% (herediter), and others are sporadic : 90 % (non-herediter)
6 Tumor = Cancerr???CYSTSContain: Liquid/SemisolidLUMPBENIGNContain: Solid/massTUMORMALIGNANTCANCERREMEBER: Every tumor must be considered malignant, until proven malignant/benign
8 Cancer is a gen disease 1.Body consist of billion cells 2.Inside the cells there is nucleolus3.Inside the nucleolus there areChromosom4.Chomosom consist of genes5.Gene are forms of DNA
9 DNA-Deoxyribonucleic Acid Is blue print that contain instruction of orgnism “creation” define human characteristic: skin color, eye color, etc.DNA consist of nucleotideNucleotide: sugar+ phosphat + base4 types of base: thymine (T), adenine (A), guanine (G), and cytosine (C)The fastest computer in the world (2006):IBM Blue Gene/L supercomputer
10 Everyday There are 20.000 DNA damaged Repaired by DNA repair gene Small part of gene ,can’t be repairedThis is the starting point of cancer
11 CancerOccur due to somatic mutation accumulation in genes that have role in cancer, such as:OncogenesTumor supressor genesMismatch repair genesCarcinogenesis process of the tumor or neoplasm developmentCarsinogen The cause of cancer
12 Carsinogenesis Defect of Genetic Control Tumor suppressor Growth promotingoncogenesDNA repairgeneDefectMutationAmplificationMutationInaktivationApoptosisDefectDefect ofGenetic Control
13 OnkogenesType of proto-onkogene mutation: point, translocation, amplification, insertion and deletionCause cell growth or survival become dominan exceed the activity of other normal genesSomatic mutation of proto-onkogene:Occur in various tumor in humanOccur during carcinogenesis processUsually, together with other mutations (tumor supresor genes and DNA repair genes)
14 Tumor Supressor Genes Failed in DNA repair Occur two hits mutations during carcinogenesis all of gene functions are diminishedp53 protein: guardian of the genomeRegulation of mitosis cycleDetect and repair DNA damageRegulation of apoptosisMutation can be hereditary
15 DNA Repair Genes 1. Repair DNA damaged 2. If there is Silencing mismatch repair gene cause by somatic DNA methylation
16 Cancer Cell Development Comes from one normal ‘stem cell’ change to be a tumor cell gradually1 cell divide to be 2 – 4 – and so on different one and others showing the cell heterogenity
18 Carsinogenesis Multistep Inisiation:Permanent change in target cell DNAPromotion:Epigenetic change selectivelly influence cell proliferation that has done inisiationProgression:Cell cancer development that shown autonomy growth, invasive progression, and metastasis.
24 Chemical CarcinogenMostly in forms pro-carsinogen need to be metabolise in body to become active( carcinogen)Convert lipophilic component water soluble metabolite (hydrophilic) can be excreted by urine or bile
26 CANCER Chemical Absorption Distribution Biotransformation (liver, kidney, lung)Excretion(liver, kidney, lung)Activation:Genotoxic& Non-genotoxic mechanismInactivationHypermutabilityGene instabilityLoss of proliferation controlResistance to apoptosisAltered signal transductionCANCERGene Damage
27 Chemical Carcinogens Group Example Cancer Polycyclic aromatic hydrocarbon(HPA)Cigarette smoke, tobacco, grilled meat, smoked meat/fishSkin, lung, gaster, liverAromatic amine and azo dyesTextile dyesliver, vesicaNicotinecigaretteLung, oral, respiratory tractHalogenated compoundDioxin: heated plastic, PVC, bleaching agents for paperKidney, lung, liverArsenicSoil, water, plant, cosmetic product, seafood, cigaretteSkin, lung, liverNitrosaminePreservatives, coloring agent for meatNasopharynx, esophagus, gaster, oralAlcoholBeverages containing alcoholOropharynx, larynx, esophagus, liver, colon, and breast
28 Chemical carcinogenCigarette> 4000 chemical agents
31 Viral Carcinogen Viral oncogenicDNA and RNA DNA virustumor supressor gene inactivation (p53, Rb)HPV 16, 18, 31cervical cancerEBV Nasopharynx cancer, Burkitt lymphoma, Hodgkin DiseaseHepatitis B virushepatomaCMV and herpes kaposi sacoma (AIDS)RNA virus onkogene activationHLTV 1T cell Leukemia, B cell lymphomaHepatitis C virushepatoma
32 Mekanisme Virus DNADNA virus contain ds-DNA that can be integrated partially or fully with host chromosom if it lasts longer, it can give rise to mutations
33 Oncogenic DNA virus and its Product Virus Gene Product Cell TargetAdenovirusSV40PolyomavirusPapillomavirusE1A E1BRb p53Large T antigen Large T antigen Middle T antigenRb, p53 Rb Src, PI3KE7 E6 E5Rb p53PDGF receptor
35 Spectrum of Cervical Epithelial Changes due to HPV infection Normal CervixHPV Infection/CIN* 1CIN 2 / CIN 3 /Cervical CancerKey PointIntegration of HPV into the DNA of the infected host cell is commonly associated with high-risk oncogenic HPV types1 and is linked to the activity of E6 and E7 proteins.2BackgroundIn benign HPV-associated skin lesions, the HPV virus maintains its genome as episomes at low copy numbers (10–200 copies/cell) in the basal cells of the epithelium separate from the host cell DNA. To maintain its viral DNA as an episome, viral E1 and E2 proteins are expressed. Failure to express E1 leads to the integration of the HPV genome into the host cell chromosome.3Integration of HPV into the DNA of the infected host cell is commonly associated with high-risk oncogenic HPV types1 and is considered an important step in tumor progression.2 In malignant HPV-associated skin lesions, HPV DNA integration into the host cell’s chromosome regularly occurs through a break in the viral genome around the E1/E2 region. Integration-mediated disruption of E2 may trigger uncontrolled expression of E6 and E7, resulting in cellular transformation.2The E6 protein associates with the tumor suppressor protein p53 and promotes proteolytic destruction of the protein. This leads to malignant transformation and loss of regulated cell growth. The E7 protein associates with the retinoblastoma protein (pRB), which inactivates the cell cycle restriction function of this protein.2References1. Gallo G, Bibbo M, Bagella L, et al. Study of viral integration of HPV-16 in young patients with LSIL. J Clin Pathol. 2003;56:532–536.2. Syrjänen KJ, Syrjänen SM. Molecular biology of papillomaviruses. In: Papillomavirus Infections in Human Pathology. Chichester, United Kingdom: John Wiley & Sons, Inc.; 2000:11–51.3. Doorbar J. The papillomavirus life cycle. J Clin Virol. 2005;32(suppl):S7–S15.*CIN = cervical intraepithelial neoplasiaAdapted from Goodman A, Wilbur DC. N Engl J Med. 2003;349:1555–1564.
36 Important Function of HPV Protein Six early Gene (E) regulate mRNA virus synthesis ans virus genome replicationE6 & E7 important in cancer processE6 disrupt supressor tumor p53 proteinE7 inactivate Retinoblastoma proteinE2 suppress E6 & E7 expressionLate Gene (L) code protein that involved in viral kapsid assemblyL1 major capsidL2 kapsid minorDestruction of p53 will prevent apoptosis of cells with damaged/abnormal DNA and thus will facilitate the accumulation of mutations.Inactivation of Retinoblastoma results in maintaining the maturing cells in a “proliferative mode” such that the DNA replication machinery of the host cell will continue to work.
37 Cell Division Cycle Cell division cycle keep going with gene mutation Cycle cell consist of 4 phase:Phase Gap 1 (preparation)Phase Sintesis (DNA synthesis)Phase Gap 2 (Division preparation)Phase Mitosis (one cell divide to be 2 cells)Phase G 0 = resting phase
40 RNA Virus MechanismRNA virus infect cellgenetic material of RNA virus become DNA pro-virus unite with host DNAGenetic material of RNA can bring part of infected host genetic material v-onkogeneV-oncogene can be transferred to another cell's genetic material (transduction)
44 UV Radiation Wave length: 280-320 nm UVB : BCC, SCC UVC: 1 part per million UVClethalUVA: good penetration but poor absorbtion in DNA.Related with skin cancer kulit (SCC, BCC, and melanoma maligna)especially in white peopleBCC = basal cell carcinomaSCC=squamous cell carcinoma
46 UV Radiation Carcinogenesis Mechanism Carsinogenesis occur if:P53 mutationcell-cycle arrest not happen, disrupt DNA repair excessive proliferationDisregulation of pro-apoptosis and anti apoptosis apoptosis not happenimmortalSKIN CANCER
47 Radiation Carcinogen Ionizing radiationradiotherapy, radiodiagnostic Carsinogenesis mechanism:Direct cell/macro-molecule damageProduce free radicalEffect:Enzyme inactivation, protein changesBroken/translocation/point mutation of inisiatorInhibit cellular immunitypromotor
49 Hormone1. Is proven as a risk factor of several cancer: breast, endometrium, ovary, prostat, thyroid, testis, bone.2. Carcinogenesis mechanism of hormone: cause excessive stimulation of hormone to affected organ by its receptor stimulate proliferation
50 Hormone & Breast Cancer Estrogen-2 (Estradiol) :Has role in cell growth and specific organ function.More than 100 years ago, it’s been known relation of estrogen and breast cancerEstrogen effect is mediated by a protein that called estrogen receptor (ER ).
51 Estradiol & other steroid hormone stimulate breast cell proliferation facilitate mutation / genetic abnormality expressionHenderson BE, Bernstein L, Ross R. Etiology of cancer: hormonal factors. In: DeVita VT, Hellman S, Rosenberg SA. Principles & practice of oncology, fifth edition. Philadelphia,2007.
52 Estrogen Signaling Pathway Estrogen binds to ER in cytoplasmE-ER complex go to nucleusBinds with Estrogen Response Element (ERE) in DNAIt’s called classic pathway/genomic/ nuclear-initiated steroid signaling(NISS)
54 Nutrition Carcinogen Nutrition: Can be carsinogenic (negative side)Can be inhibit carsinogenesis, and even can be part of cancer therapy (positive side)Carsinogenic and anticarsinogenic of food role in every carcinogenesis step
55 Nutrition CarsinogenNutrients that affect cancer occurrence can be divided into 2 categories :Micro componentMacro componen and total caloric intakeAlso, can be divided into:Genotoxic agentsNon-genotoxic agents
56 Genotoxic Cause DNA damage: Generally in the form of micro components Point mutations, deletion and insertion, recombination, rearrangements and amplification, aberrant chromosomesGenerally in the form of micro componentsMost common: Heterocyclic amines (HCA) comes from protein, especially overcooked meat.
57 Non-genotoxicCarsinogenesis mechanism has not been clearly understandingIncorporate with genotoxic agents in carsinogenesis processGenerally, in the form of macro components, and require higher and longer exposureExample: fat (breatst cancer and colon cancer), Natrium chlorida (ca gaster)
58 Genotoxic and Nongenotoxic Mechanism DNA Adduct(DNA + Carcinogen)Non-genotoxicInitiationMutationDNA-repairNormal DNAAbnormal DNA and cell replicationPromoterPromotionApoptosisObesitasPhysical activityDietIntestinal bacterial coloniesHormoneGrowth factorImmune systemPrecancerous lesionProgressionInvasive lesion
59 Nutrition Carsinogen Other micro components Alphatoxin B1 (AFB1) from mold Aspergillus flavus legumes, corns, soybeans, rice, milk, and cheese HepatomaHydrazin and agaritin compound in undercooeked champignon mushroom bone carcinoma, gaster, liver, and lung cancerGlucoside in ferns (Pterigium sp,. Bracken fern) vesica, gasterm breast cancer
60 Nutrition carsinogen Macro Nutrition: Fat consumption>> positive correlation with breast, colon, prostate cancer incidenceFatty acid influence tumorigenesis through immune system (eicosanoid metabolite)Saturated fat acids in animal and unsaturated fatty acids (Ω -6 PUFA) from corn oil, sunflower seed oil associated with carsinogenesis & tumorigenesis
61 Summary1.Cancer is a disease start from the gene, and end with organ metastases (death) and caused by gene mutation2.Genes that play role in cancer are oncogenes, tumor suppressor genes, mismatch repair genes3.The etiology of cancer is called carsinogen, consist of chemical agents, virus, radiation, hormone, and nutrition
62 4. Some cancer can be prevented 4. Some cancer can be prevented. Information about risk factor is important.5. Cancer will be an epidemic disease, every health worker, especially doctors have to know it better.