Etiology and Risk Factor of Cancer

Noorwati SutandyoDharmais Cancer Center /Dharmais Cancer Center /

Division of Hematology-Medical OncologyDivision of Hematology-Medical OncologyDept Internal MedicineDept Internal Medicine

University of Indonesia School of MedicineUniversity of Indonesia School of Medicine

International Class May 2013

Incidence of cancer is high and going higher every Incidence of cancer is high and going higher every year year Globocan: 12.7 million new cancer cases 2008Globocan: 12.7 million new cancer cases 2008 Nearly Nearly doubledouble to 21.4 million cases by to 21.4 million cases by 20302030

Cancer Cancer causes 1 in 8 deaths causes 1 in 8 deaths worldwide worldwide becoming becoming a global pandemica global pandemic Cancer is killing Cancer is killing moremore people in the developing people in the developing

world world than HIV/AIDS, tuberculosis, and malaria than HIV/AIDS, tuberculosis, and malaria combinedcombined

CANCER CANCER

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).

Top 10 Malignancy in Dharmais NCC in Male 2005-2007

2.7%

2.9%

3.0%

3.9%

6.3%

7.5%

9.5%

10.1%

13.1%

13.8%

0.0% 2.0% 4.0% 6.0% 8.0% 10.0

%

12.0

%

14.0

%

16.0

%

Soft Tissue

Skin

Prostate Gland

Oral Cavity

Hepar

Leukemia

Lymph Nodes

Colorectum

Pharynx

Bronchus and Lung

Topo

grap

hy

Percent

Top 10 Malignancy in Dharmais NCC

in Female 2005-2007

2.5%

2.8%

2.9%

3.0%

3.2%

3.5%

3.7%

5.6%

17.6%

41.2%

0.0% 10.0% 20.0% 30.0% 40.0% 50.0%

Corpus Uteri

Bronchus and Lung

Pharynx

Leukemia

Lymph Nodes

Thyroid Gland

Colorectum

Ovary

Cervix Uteri

Breast

Topo

grap

hy

Percent

Cancer DefinitionCancer Definition

CCananccer er isis abnormalabnormal growth of growth of cells. cells. Cancer cells Cancer cells will growthwill growth fastfast even with limited of even with limited of

space and nutrition. space and nutrition. Heterogenous:Heterogenous: more than 100 different types of more than 100 different types of

cancercancer Some are Some are familialfamilial : 5-10% : 5-10% (herediter), and others (herediter), and others

are are sporadic sporadic : 90 % : 90 % (non-herediter)(non-herediter)

Tumor = Cancerr???Tumor = Cancerr???

REMEBER: Every REMEBER: Every tumor must be considered tumor must be considered malignant, malignant, until proven malignant/benign until proven malignant/benign

LUMP

Contain: Liquid/Semisolid

Contain: Solid/mass

CYSTS

TUMOR

BENIGN

MALIGNANT

CANCER

Cancer CharacteristicCancer Characteristic

1.Body consist of 1.Body consist of billion cellsbillion cells

2.Inside the cells 2.Inside the cells there is nucleolusthere is nucleolus

3.Inside the 3.Inside the nucleolus there are nucleolus there are

ChromosomChromosom

4.Chomosom 4.Chomosom consist of genesconsist of genes

5.Gene are forms of 5.Gene are forms of DNADNA

DNA-Deoxyribonucleic AcidDNA-Deoxyribonucleic Acid Is Is blue printblue print thatthat contain instruction contain instruction

of orgnism “creation” of orgnism “creation” define human define human characteristic: skin color, eye color, characteristic: skin color, eye color, etc.etc.

DNA consist of DNA consist of nucleotidenucleotide Nucleotide: Nucleotide: sugar+ phosphat + basesugar+ phosphat + base 4 types of base4 types of base: thymine (T), : thymine (T),

adenine (A), guanine (G), and adenine (A), guanine (G), and cytosine (C)cytosine (C)

The fastest computer in the world (2006): IBM Blue Gene/L supercomputer

EverydayEveryday

There are 20.000 DNA damaged There are 20.000 DNA damaged Repaired by DNA repair geneRepaired by DNA repair gene Small part of gene ,can’t be repairedSmall part of gene ,can’t be repaired This is the starting point of cancerThis is the starting point of cancer

CancerCancer

Occur due to Occur due to somatic mutation accumulationsomatic mutation accumulation in in genes that have role in cancer, such as: genes that have role in cancer, such as: OncogenesOncogenes Tumor supressor genesTumor supressor genes Mismatch repair genesMismatch repair genes

CarcinogenesisCarcinogenesis process of the tumor or process of the tumor or neoplasm developmentneoplasm development

Carsinogen Carsinogen The cause of cancerThe cause of cancer

CarsinogenesisCarsinogenesis

Growth promotingGrowth promotingoncogenesoncogenes

Tumor suppressorTumor suppressorgenesgenes

Defect ofGenetic Control

MutationInaktivation

MutationAmplification

DefectDefect

DefectDefect

DNA repairgene

ApoptosisApoptosis

OnkogenesOnkogenes

Type of proto-onkogene mutation:Type of proto-onkogene mutation: point, point, translocation, amplification, insertion and translocation, amplification, insertion and deletiondeletion

Cause cell Cause cell growth or survival growth or survival become dominabecome dominann exceed the activity of other normal genes exceed the activity of other normal genes

Somatic Somatic mutation of proto-onkogenemutation of proto-onkogene:: Occur in various tumor in humanOccur in various tumor in human Occur during carcinogenesis processOccur during carcinogenesis process UUsually, together with other mutations (tumor sually, together with other mutations (tumor

supresor genes and DNA repair genes)supresor genes and DNA repair genes)

Tumor Supressor GenesTumor Supressor Genes

Failed in DNA repairFailed in DNA repair OccurOccur two hits mutations two hits mutations during during

carcinogenesiscarcinogenesis all of gene functions are all of gene functions are diminisheddiminished

p53 protein: p53 protein: guardian of the genomeguardian of the genome Regulation of mitosis cycleRegulation of mitosis cycle Detect and repair DNA damageDetect and repair DNA damage Regulation of apoptosisRegulation of apoptosis

Mutation can be hereditaryMutation can be hereditary

DNA Repair GenesDNA Repair Genes

1. Repair DNA damaged1. Repair DNA damaged

2. If there is 2. If there is Silencing mismatch repair gene Silencing mismatch repair gene cause by cause by somatic DNA methylationsomatic DNA methylation

Cancer Cell DevelopmentCancer Cell Development

Cancer cellCancer cell Comes from one Comes from one

normal normal ‘stem cell’ ‘stem cell’ change tochange to be be a a tumor tumor cell cell graduallygradually

1 cell divide to be 2 – 1 cell divide to be 2 – 4 – and so on different 4 – and so on different one and others one and others showing the showing the cellcell heterogenityheterogenity

Carsinogenesis MultistepCarsinogenesis Multistep

Inisiation:Inisiation: Permanent change in target cell DNAPermanent change in target cell DNA

Promotion:Promotion: Epigenetic change selectivelly influence cell Epigenetic change selectivelly influence cell

proliferation that has done inisiationproliferation that has done inisiation Progression:Progression:

Cell cancer development that shown Cell cancer development that shown autonomy growth, invasive progression, and autonomy growth, invasive progression, and metastasis. metastasis.

Cancer EtiologyCancer Etiology

Several factors that play a Several factors that play a role:role:

•AgeAge•GenetiGeneticc•Hormone Hormone •Immnune systemImmnune system•ObesitasObesitas•Chemical agents Chemical agents (cigarette)(cigarette)•DietDiet•RadiaRadiation tion & UV& UV light light•VirusVirus•StressStress

AgeAge Generally, the risk increasesGenerally, the risk increases in in older personolder person

BUT, cancer can occur to BUT, cancer can occur to anyone, at any age.anyone, at any age.

Tendency, increasing in Tendency, increasing in younger ageyounger age

CarsinogensCarsinogens

Everything causes cancer by causing DNA changes mutagenicmutagenic

Type of carcinogensType of carcinogens Chemical agentsChemical agents VirusVirus RadiationRadiation HormoneHormone NutritionNutrition

CHEMICAL AGENTCHEMICAL AGENT

Chemical CarcinogenChemical Carcinogen

Mostly in forms Mostly in forms pro-carsinogenpro-carsinogen need to need to be be metabolisemetabolise in body to become in body to become activeactive

(( carcinogen carcinogen)) Convert Convert lipophiliclipophilic component component water water

soluble metabolite soluble metabolite (hydrophilic)(hydrophilic) can be can be excreted by urine or bileexcreted by urine or bile

Drugs Metabolism PathwayDrugs Metabolism Pathway

Chemical

Absorption

Distribution

Biotransformation (liver, kidney, lung)

Activation:

Genotoxic

& Non-genotoxic mechanism

InactivationExcretion

(liver, kidney, lung)

Gene Damage

Altered signal transduction

•Hypermutability

•Gene instability

•Loss of proliferation control

•Resistance to apoptosis

CANCER

Chemical CarcinogensChemical CarcinogensGroup Example Cancer

Polycyclic aromatic hydrocarbon

(HPA)

Cigarette smoke, tobacco, grilled meat, smoked meat/fish

Skin, lung, gaster, liver

Aromatic amine and azo dyes

Textile dyes liver, vesica

Nicotine cigarette Lung, oral, respiratory tract

Halogenated compound

Dioxin: heated plastic, PVC, bleaching agents for paper

Kidney, lung, liver

Arsenic Soil, water, plant, cosmetic product, seafood, cigarette

Skin, lung, liver

Nitrosamine Preservatives, coloring agent for meat

Nasopharynx, esophagus, gaster, oral

Alcohol Beverages containing alcohol

Oropharynx, larynx, esophagus, liver, colon, and breast

Chemical carcinogenChemical carcinogen

CigaretteCigarette> 4000 chemical agents> 4000 chemical agents

Chemical Carcinogen Chemical Carcinogen MechanismMechanism

CigaretteCigarette

VIRAL CARCINOGENVIRAL CARCINOGEN

Viral CarcinogenViral Carcinogen Viral oncogenicViral oncogenicDNA and RNADNA and RNA DNA virusDNA virustumor supressor gene inactivation tumor supressor gene inactivation

(p53, Rb)(p53, Rb) HPVHPV 16, 18, 31 16, 18, 31cervical cancercervical cancer EBVEBV Nasopharynx cancer, Burkitt lymphoma, Nasopharynx cancer, Burkitt lymphoma,

Hodgkin DiseaseHodgkin Disease Hepatitis BHepatitis B virus virushepatomahepatoma CMVCMV and herpes and herpes kaposi sacoma (AIDS)kaposi sacoma (AIDS)

RNA virusRNA virus onkogene activationonkogene activation HLTV 1HLTV 1T cell Leukemia, B cell lymphomaT cell Leukemia, B cell lymphoma Hepatitis C Hepatitis C virusvirushepatomahepatoma

Mekanisme Virus DNAMekanisme Virus DNA

DNA virus contain DNA virus contain dsds-DNA -DNA that can be that can be integrated partially or fully integrated partially or fully with with host host chromosomchromosom if it lasts longer, it can give rise to mutations

Oncogenic DNA virus and its Oncogenic DNA virus and its ProductProduct

Virus Gene Product Cell Target

Adenovirus

SV40Polyomavirus

Papillomavirus

E1A E1B

Large T antigen Large T antigen Middle T antigen

E7 E6 E5

Rb p53

Rb, p53 Rb Src, PI3K

Rb p53 PDGF receptor

Spectrum of Cervical Epithelial Changes due to HPV infection

*CIN = cervical intraepithelial neoplasia

Adapted from Goodman A, Wilbur DC. N Engl J Med. 2003;349:1555–1564.

Normal Normal CervixCervix

HPV Infection/HPV Infection/CIN* 1CIN* 1

CIN 2 / CIN 3 /CIN 2 / CIN 3 /Cervical CancerCervical Cancer

Important Function of HPV Important Function of HPV ProteinProtein

Six early Gene (E)Six early Gene (E) regulate mRNA virus synthesis regulate mRNA virus synthesis ans virus genome replicationans virus genome replication

E6E6 & & E7 E7 important in cancer processimportant in cancer process• E6E6 disrupt disrupt supressor tumor p53 supressor tumor p53 proteinprotein• E7E7 inactivate inactivate Retinoblastoma Retinoblastoma proteinprotein

E2E2 suppress E6 & E7 expressionsuppress E6 & E7 expression

Late Gene (L)Late Gene (L) code protein that involved in viral code protein that involved in viral kapsid kapsid assemblyassembly

L1L1 major capsidmajor capsid L2L2 kapsid minorkapsid minor

Cell division cycle keep Cell division cycle keep going with gene mutationgoing with gene mutation

Cycle cell consist of Cycle cell consist of 44 phasephase: :

PhasePhase GGap 1 (ap 1 (preparationpreparation)) Phase Phase SSintesis (DNAintesis (DNA

synthesissynthesis)) PhasePhase GGap 2 (ap 2 (Division Division

preparationpreparation)) Phase Phase MMitosis (itosis (one cell one cell

divide to be 2 cellsdivide to be 2 cells))

Phase Phase GG 0 =0 = resting phase resting phase

Cell Division Cycle

RNA Virus MechanismRNA Virus Mechanism

RNA virus infect cellRNA virus infect cellgenetic material of genetic material of RNA virus become DNA pro-virusRNA virus become DNA pro-virus unite unite with host DNAwith host DNA

Genetic material of RNA can bring part of Genetic material of RNA can bring part of infected host genetic material infected host genetic material v-v-onkogeneonkogene

V-oncogene can be transferred to another cell's genetic material ( (transductiontransduction))

RNA Virus MechanismRNA Virus Mechanism

Oncogenic RNA virus Oncogenic RNA virus create onkogen by:create onkogen by: gettinggetting modificationmodificationCellular gene Cellular gene deregulationderegulation

proto-onkogenproto-onkogen

RADIATION CARCINOGENRADIATION CARCINOGEN

RadiationRadiation

RadiationRadiation Non-ionizingNon-ionizingUVUV IonizingIonizingradio-diagnostic, radio-therapeuticradio-diagnostic, radio-therapeutic

Wave length: 280-320 nm280-320 nmUVB : BCC, SCCUVC: 1 part per million UVClethalUVA: good penetration but poor absorbtion in DNA.

Related with skin cancer kulit Related with skin cancer kulit ((SCC, BCC, and melanoma SCC, BCC, and melanoma malignamaligna))especially in white especially in white peoplepeople

UV RadiationUV Radiation

UV Radiation Carcinogenesis UV Radiation Carcinogenesis MechanismMechanism

CANCER

NORMAL

UV Radiation Carcinogenesis UV Radiation Carcinogenesis MechanismMechanism

CarsinogenesisCarsinogenesis occur if: occur if: P53 mutationP53 mutationcell-cycle arrest not happen, cell-cycle arrest not happen,

disrupt DNA repair disrupt DNA repair excessive proliferationexcessive proliferation Disregulation of pro-apoptosis and anti Disregulation of pro-apoptosis and anti

apoptosisapoptosis apoptosis not happen apoptosis not happenimmortalimmortal

SKIN CANCER

Radiation CarcinogenRadiation Carcinogen Ionizing radiationIonizing radiationradiotherapy, radiotherapy,

radiodiagnosticradiodiagnostic Carsinogenesis mechanismCarsinogenesis mechanism::

Direct cell/macro-molecule damageDirect cell/macro-molecule damage Produce free radicalProduce free radical

Effect:Effect: Enzyme inactivation, Enzyme inactivation, protein changesprotein changes Broken/translocation/point mutation of Broken/translocation/point mutation of

inisiatorinisiator Inhibit cellular immunityInhibit cellular immunitypromotorpromotor

HORMONAL HORMONAL CARCINOGENESISCARCINOGENESIS

HormoneHormone

1. Is proven as a risk factor of several 1. Is proven as a risk factor of several cancer: cancer: breast, endometrium, ovary, breast, endometrium, ovary, prostat, thyroid, testis, bone.prostat, thyroid, testis, bone.

2. Carcinogenesis mechanism of hormone: 2. Carcinogenesis mechanism of hormone: cause cause excessive stimulation of hormone excessive stimulation of hormone to to affected organ affected organ by its receptorby its receptor stimulate stimulate proliferationproliferation

Hormone & Breast CancerHormone & Breast Cancer

Estrogen-2 (Estradiol) :Estrogen-2 (Estradiol) : Has role in Has role in cell growth cell growth and specific organ and specific organ

function.function. More than 100 years ago, it’s been known More than 100 years ago, it’s been known

relation of estrogen and breast cancerrelation of estrogen and breast cancer Estrogen effect is mediated by a protein Estrogen effect is mediated by a protein

that called that called estrogen receptor (ER ).estrogen receptor (ER ).

Estradiol & other steroid hormone stimulate breast cell proliferation facilitate mutation / genetic abnormality

expression

Henderson 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.

Estrogen Signaling PathwayEstrogen Signaling Pathway Estrogen binds to ER in Estrogen binds to ER in

cytoplasmcytoplasm E-ER complex go to E-ER complex go to

nucleusnucleus Binds with Binds with Estrogen Estrogen

Response ElementResponse Element (ERE) in DNA(ERE) in DNA

It’s called It’s called classic classic pathwaypathway/genomic/ /genomic/ nuclear-initiated steroid nuclear-initiated steroid signaling(NISS)signaling(NISS)

NUTRITION NUTRITION CARCINOGENESISCARCINOGENESIS

Nutrition CarcinogenNutrition Carcinogen Nutrition:Nutrition:

Can be Can be carsinogeniccarsinogenic (negative side)(negative side) Can beCan be inhibitinhibit carsinogenesis, and even can carsinogenesis, and even can

be part of be part of cancer therapy cancer therapy (positive side)(positive side) Carsinogenic and anticarsinogenic of Carsinogenic and anticarsinogenic of

foodfood role in every carcinogenesis step role in every carcinogenesis step

Nutrition CarsinogenNutrition Carsinogen

Nutrients that affect cancer occurrence can be divided into 2 categories :: MicroMicro componentcomponent MacroMacro componen and total caloric intake componen and total caloric intake

Also, can be divided into:Also, can be divided into: GenotoxicGenotoxic agentsagents Non-genotoxic Non-genotoxic agentsagents

GenotoxicGenotoxic Cause Cause DNA damageDNA damage: :

Point mutationsPoint mutations, deletion and insertion, , deletion and insertion, recombination, recombination, rearrangementsrearrangements and and amplification, aberrant chromosomesamplification, aberrant chromosomes

Generally in the form of Generally in the form of micro componentsmicro components Most common: Most common: Heterocyclic aminesHeterocyclic amines (HCA) (HCA)

comes from protein, especially overcooked comes from protein, especially overcooked meat.meat.

Non-genotoxicNon-genotoxic

Carsinogenesis mechanism has not been clearly Carsinogenesis mechanism has not been clearly understandingunderstanding

• Incorporate with genotoxic agents in Incorporate with genotoxic agents in carsinogenesis processcarsinogenesis process

Generally, in the form of Generally, in the form of macro componentsmacro components, , and require higher and longer exposureand require higher and longer exposure

Example: Example: fatfat (breatst cancer and colon cancer), (breatst cancer and colon cancer), Natrium chlorida Natrium chlorida (ca gaster)(ca gaster)

Initiation

Promotion

Progression

DNA Adduct

(DNA + Carcinogen)

Mutation

DNA-repair Normal DNA

Abnormal DNA and cell replication

Precancerous lesion

Invasive lesion

Apoptosis

Promoter

Obesitas

Physical activity

Diet

Intestinal bacterial colonies

Hormone

Growth factor

Immune system

Genotoxic and Nongenotoxic Genotoxic and Nongenotoxic Mechanism Mechanism

Genotoxic

Non-genotoxic

Nutrition CarsinogenNutrition Carsinogen

Other micro componentsOther micro components Alphatoxin B1 Alphatoxin B1 (AFB1) from mold (AFB1) from mold Aspergillus flavus Aspergillus flavus

legumes, corns, soybeans, rice, milk, and cheese HepatomaHepatoma

Hydrazin and agaritin Hydrazin and agaritin compound in undercooeked compound in undercooeked champignon mushroomchampignon mushroom bone carcinoma, gaster, bone carcinoma, gaster, liver, and lung cancerliver, and lung cancer

GlucosideGlucoside in in ferns (ferns (Pterigium sp,.Pterigium sp,. Bracken fern)Bracken fern) vesica, gasterm breast cancervesica, gasterm breast cancer

Nutrition carsinogenNutrition carsinogen

Macro Nutrition:Macro Nutrition: FatFat consumption>> consumption>> positive correlation with positive correlation with

breast, colon, prostate cancer breast, colon, prostate cancer incidenceincidence Fatty acid influence tumorigenesis through Fatty acid influence tumorigenesis through

immune system immune system (eicosanoid metabolite)(eicosanoid metabolite) Saturated fat acids in Saturated fat acids in animal animal andand unsaturatedunsaturated

fatty acids (fatty acids (ΩΩ -6 PUFA) -6 PUFA) from corn oil, from corn oil, sunflower seed oilsunflower seed oil associated with associated with carsinogenesis & tumorigenesiscarsinogenesis & tumorigenesis

SummarySummary

1.1.Cancer is Cancer is a a diseasedisease start from the gene, start from the gene, and end with organ metastases (death)and end with organ metastases (death) and caused by and caused by gene mutationgene mutation

2.2.Genes that play role in cancer are Genes that play role in cancer are oncogenes, tumor suppressor genes, oncogenes, tumor suppressor genes, mismatch repair mismatch repair genesgenes

3.3.The etiology of cancer is called The etiology of cancer is called carsinogencarsinogen, consist of , consist of chemical agents, chemical agents, virus, radiation, hormone, and nutritionvirus, radiation, hormone, and nutrition

4. Some cancer 4. Some cancer can be preventedcan be prevented. . Information about risk factor is important.Information about risk factor is important.

5. Cancer will be an 5. Cancer will be an epidemic diseaseepidemic disease, , every health worker, especially doctors every health worker, especially doctors have to know it better.have to know it better.