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Cancer Epidemiology I
Professor Tarek Tawfik Amin
amin55@myway.com
What is cancer?
• Cancer is a group of diseases characterized by
uncontrolled growth and spread of abnormal cells.
• Cance...
Biologic Basis
Normal
cell
Initiated
cell
Pre-cancerous
cell
CANCER
Initiation Promotion Progression
Rates to assess burden
• Incidence
• Prevalence
• Specific
• Crude
• Adjusted/Standardized
• SMR/SIR
Incidence: No. of new...
Global burden
• The global burden of cancer continues to
increase:
- The aging and growth of the world population
- an inc...
http://www.globocan.iarc.fr
assessing the cancer burden (incidence-
mortality)
Egypt
All cancers excl. non-melanoma skin cancer
Year
Estimated
number of new
cancers(all
ages)
Male Female Both sexes
201...
Egypt
All cancers excl. non-melanoma skin cancer
Year
Estimated
number of
cancer deaths
(all ages)
Male Female Both sexes
...
Estimated numbers (thousands) Men Women Both sexes
Cases Deaths 5-year prev. Cases Deaths 5-year prev. Cases Deaths 5-year...
Estimated age-
standardised
rates (World) per
100,000
At a glance
There were 14.1 million new cancer cases, 8.2 million ca...
Estimated Cancer Incidence Worldwide in 2012: Men 
Estimated age-standardised rates (World) per 100,000
Trends in incidence of cancer in selected countries: age-standardised rate (W) per
100,000, men
GLOBOCAN 2012 (IARC) , Sec...
Estimated Cancer Mortality Worldwide in 2012: Men 
GLOBOCAN 2012 (IARC) , Section of Cancer Surveillance (24/2/2015)
Trends in mortality from cancer in selected countries: a...
Estimated Cancer Incidence Worldwide in
2012: Women
GLOBOCAN 2012 (IARC) , Section of Cancer Surveillance (24/2/2015)
Estimated Cancer Mortality Worldwide in
2012: Women
 
MORE DEVELOPED AREAS LESS DEVELOPED AREAS
INCIDENCE MORTALITY INCIDENCE MORTALITY
ASR
CUMULATIVE 
RISK (%) 
ASR
CUMULATI...
More developed                                             Females                                          less developed...
  INCIDENCE MORTALITY
  MALE FEMALE OVERALL MALE FEMALE OVERALL
Eastern Africa 121.2 125.3 122.8 105.4 95.9 99.9
Middle Af...
Cancer incidence and mortality by site and gender US 2014
CA: A Cancer Journal for Clinicians Volume 61, Issue 2, pages 69-90, 4 FEB 2011 DOI: 10.3322/caac.20107
http://onlinelibra...
Global burden of cancer 2008
• Based on the GLOBOCAN 2008 estimates, about 12.7
million cancer cases and 7.6 million cance...
• Breast cancer is the most frequently diagnosed cancer and the
leading cause of cancer death among females (23% of the to...
• Although overall cancer incidence rates in the developing world are
half those seen in the developed world in both sexes...
Global cancer statistics: Age‐Standardized Breast Cancer Incidence and Mortality Rates by World Area
CA: A Cancer Journal ...
Global cancer statistics: Age‐Standardized Colorectal Cancer Incidence Rates by Sex and World Area.
CA: A Cancer Journal f...
Global cancer statistics: Age‐Standardized Lung Cancer Incidence Rates by Sex and World Area
CA: A Cancer Journal for Clin...
Global cancer statistics: Age‐Standardized Prostate Cancer Incidence and Mortality Rates by World Area
CA: A Cancer Journa...
Global cancer statistics: Age‐Standardized Stomach Cancer Incidence Rates by Sex and World Area
CA: A Cancer Journal for C...
Global cancer statistics: Age‐Standardized Cervical Cancer Incidence and Mortality Rates by World Area.
CA: A Cancer Journ...
Global cancer statistics: Age‐Standardized Liver Cancer Incidence Rates by Sex and World Area.
CA: A Cancer Journal for Cl...
Global cancer statistics: Age‐Standardized Urinary Bladder Cancer Incidence Rates by Sex and World
Area
CA: A Cancer Journ...
Global cancer statistics: Age‐Standardized Esophageal Cancer Incidence Rates by Sex and World Area
CA: A Cancer Journal fo...
Global cancer statistics: Age‐Standardized Non‐Hodgkin Lymphoma Incidence Rates by Sex and World
Area
CA: A Cancer Journal...
Global cancer statistics: Age‐Standardized Oral Cavity Cancer Incidence Rates by Sex and World Area
CA: A Cancer Journal f...
Global cancer statistics: Age‐Standardized Nasopharyngeal Cancer Incidence Rates by Sex and World
Area
CA: A Cancer Journa...
The 10 Most Commonly Diagnosed Cancers: 2012 Estimates
Total Number and Percentage of New Cases Diagnosed per Year, Worldw...
Global cancer statistics: Proportion of Infants Covered by National Infant Hepatitis B Immunization
Programs, 2008
CA: A C...
MYTH
Cancer is a disease of developed
countries
FACT
Low and middle-income countries
now bear a majority share of the
burd...
Globocan 2008
Less Developed versus More Developed Countries
Cancer IncidenceCancer Incidence Cancer DeathsCancer Deaths
L...
Percent of Worldwide Cancers Diagnosed
in Developing Countries
• 1970 – 15%
• 2008 – 56%
• 2030 – 70%
•Ferlay J, et al. GL...
Most Common Cancer Site in Females Globally
Source: GLOBOCAN 2008
Source: Knaul, Arreola, Mendez. estimates based on IHME, 2011.
The Cancer Transition in Low and Middle Income Countries (L...
Carcinogenesis
Carcinogenesis
• Thetransformation of normal to neoplastic
cellsiscaused by both endogenousand
exogenousfactors, including...
Latency
For infectious disease, the initial insult is the entrance of the
infectious organism into the host and the laten...
Multistage Carcinogenesis
• Two stages: Initiation and Promotion.
Theinitial two stagetheory based on the
natural history ...
Stages of Carcinogenesis
• Initiation is the first critical carcinogenic
event and it is usually a reaction between a
carc...
Stages of Carcinogenesis
• Promotion is induced by a stimulator of cell proliferation
and enhances the carcinogenic proces...
Multistage Carcinogenesis
• Three stages: Initiation, promotion, and progression.
The two stage concept was modified and t...
Tumor Growth
• In the normal proliferating tissue, a
balance between cell renewal and cell
death is strictly maintained
• ...
Human Cancer-Based Two-hit
Model
• Two-hit model. Tumor suppressor gene such as RB gene.
- Knudson (1971) suggested that a...
Human Colon Cancer Multiple
Stage Model
• Colon cancer model. The development of human
cancer is a multistage process, inv...
Early Stage versus Late
Stage
• “Early stage” versus “late stage” carcinogens in epidemiologic
stages.
- If an agent is “e...
Early Stage versus Late Stage
Molecular Genetic of Cancer
• It is now recognized that the unregulated growth of
cancer cells results from the sequential...
• Mutations can be produced by environmental mutagens
such as chemical carcinogens or radiation
• Mutations can also arise...
DNA endogenous damage and Repair
• Approximately 20,000 DNA damage lesions/cell/day
• 1 billion DNA damage lesions/human b...
Genetic Mutations and Tumor development
• Most of these mutations are of no consequence,
because they either do not affect...
Cell Transformation
• Malignant transformation involves somatic mutations that
confer a set of common properties
• It is e...
Transformed cells share common
attributes
o
Autonomous generation of mitogenic signals
o
Insensitivity to exogenous antigr...
Oncogenes
• Oncogenesarealtered version of normal
genes, termed protooncogene, that regulate
normal cell growth, different...
Mechanisms of Oncogene Action
• Growth factors(IGF-1)
• Cell surfacereceptors
• Intracellular signal transduction pathways...
Tumor Suppressor Genes
• Tumor suppressor genes are normal genes whose
products inhibit cellular proliferation.
• Loss-of ...
TumorSuppressorGenes
• A mutation that creates a deficiency of a
normal gene product that exerts a negative
regulatory con...
Carcinogens
An agent that can causecancer. The
International Agency for Research on Cancer
(IARC) classifiescarcinogensasf...
Carcinogens
• 2) Limited evidence. A positive causal association has been
observed between exposure to the agent, for whic...
Carcinogens
• 3) Inadequate evidence. Available studies are of
insufficient quality, consistency or statistical power to
p...
Carcinogens
• 4) Evidence suggesting lack of carcinogenicity. Several
adequate studies covering the full range of doses to...
Overall evaluation of carcinogen
Taking all theevidenceinto account, theagent isassigned to oneof the
following categories...
Classification of carcinogenic Agents in Relation to Their
Action on One or More Stages of Carcinogenesis
Group 1: Carcinogenic to Humans
• Tobacco Smoking
• Tobacco Products, Smokeless
• 4-Aminobiphenyl (4-ABP)
• Benzene
• Cadm...
Group 2A: Probably Carcinogenic to Humans
• Acrylonitrile
• Benzo[a]pyrene
• Benzo[a]anthracene
• 1,3-Butadiene
• Dibenz(a...
Group 2B: Possibly Carcinogenic to Humans
• Acetaldehyde
• Benzo[b]fluoranthene
• Benzo[j]fluoranthene
• Benzo[k] fluorant...
Group 2B: Possibly Carcinogenic to Humans
• Dibenzo(a,i)pyrene
• Dibenzo(a,l)pyrene
• 1,1-Dimethylhydrazine
• Hydrazine
• ...
Group 2B: Possibly Carcinogenic to Humans
• 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)
• 2-Nitropopane
• N-Nitro...
Group 2B: Possibly Carcinogenic to Humans
• Quinoline
• ortho-Toluidine
• Urethane (Ethyl Carbamate)
Group 3: Unclassifiable as to Carcinogenicity to Humans
(Limited Evidence)
• Chrysene
• Crotonaldehyde
• N-Nitrosoanabasin...
If DNA damage not
repaired
DNA damage
repaired
If loose cell cycle
control
Defected DNA
repair gene
G
S
G2
M
P53
Cyclin D1...
Chemical/environmental
carcinogens
• Smoking and lung cancer
• Sun exposure and squamous cell carcinoma of skin
• Asbestos...
Radiation
• Exposure to ultraviolet radiation (in the
form of sunlight) and squamous cell
carcinoma of skin
• Ionizing rad...
Viral factors
• HPV (human papilloma virus) and Cervix cancer
• EBV(Epstein-Barr virus) and Nasopharyngeal
cancer, Burkitt...
Precursors
• Isacondition which beassociated with the
development of cancer (Stout, 1932)
• Visiblestepsin adynamic proces...
Precursors
Two groups:
• less advanced lesions, which do not include abnormal
clones
• more advanced lesions or dysplasia,...
Significance
• Elucidation of the etiology of precursors provides
insight into etiology of the corresponding cancer
• Iden...
Thank you
Cancer Epidemiology part I
Cancer Epidemiology part I
Cancer Epidemiology part I
Cancer Epidemiology part I
Cancer Epidemiology part I
Cancer Epidemiology part I
Cancer Epidemiology part I
Cancer Epidemiology part I
Cancer Epidemiology part I
Cancer Epidemiology part I
Cancer Epidemiology part I
Cancer Epidemiology part I
Cancer Epidemiology part I
Cancer Epidemiology part I
Cancer Epidemiology part I
Cancer Epidemiology part I
Cancer Epidemiology part I
Cancer Epidemiology part I
Cancer Epidemiology part I
Cancer Epidemiology part I
Cancer Epidemiology part I
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Cancer Epidemiology part I

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Cancer Epidemiology, Cancer burden, Risk factors, Carcinogensis, Environmental factors, genetics

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Cancer Epidemiology part I

  1. 1. Cancer Epidemiology I Professor Tarek Tawfik Amin amin55@myway.com
  2. 2. What is cancer? • Cancer is a group of diseases characterized by uncontrolled growth and spread of abnormal cells. • Cancer is caused by external factors and internal factors which may act together to initiate or promote carcinogenesis.
  3. 3. Biologic Basis Normal cell Initiated cell Pre-cancerous cell CANCER Initiation Promotion Progression
  4. 4. Rates to assess burden • Incidence • Prevalence • Specific • Crude • Adjusted/Standardized • SMR/SIR Incidence: No. of new cancers occurring in a particular amount of time…per 100000 or per 1X106 Prevalence: (Not defined) No. of cases that exist at a given time Specific: age, gender, race Crude: not adjusted Adjusted/Standardized: usually for US, use US population SMR/SIR: standard mortality ratios/standard incidence ratios…SMR=200…2 fold increase of disease compared to the standard population. Survival: Several parameters
  5. 5. Global burden • The global burden of cancer continues to increase: - The aging and growth of the world population - an increasing adoption of cancer-causing behaviors, particularly smoking, in economically developing countries.
  6. 6. http://www.globocan.iarc.fr assessing the cancer burden (incidence- mortality)
  7. 7. Egypt All cancers excl. non-melanoma skin cancer Year Estimated number of new cancers(all ages) Male Female Both sexes 2012 52958 55653 108611  ages< 65 33208 36872 70080     ages>= 65 19750 18781 38531    2020 62559 66148 128707   ages< 65 38046 41352 79398    ages>= 65 24513 24796 49309    Demographic change 9601 10495 20096 ages< 65 4838 4480 9318 ages>= 65 4763 6015 10778 Population forecasts were extracted from the United Nations, World Population prospects, the 2012 revision. Numbers are computed using age-specific rates and corresponding populations for 10 age-groups. GLOBOCAN 2012 (IARC) - 25.2.2015: Egypt
  8. 8. Egypt All cancers excl. non-melanoma skin cancer Year Estimated number of cancer deaths (all ages) Male Female Both sexes 2012 39203 33097 72300    ages< 65 21141 17145 38286    ages>= 65 18062 15952 34014    2020 46671 40512 87183    ages< 65 24339 19356 43695    ages>= 65 22332 21156 43488    Demographic change 7468 7415 14883   ages< 65 3198 2211 5409    ages>= 65 4270 5204 9474 Population forecasts were extracted from the United Nations, World Population prospects, the 2012 revision. Numbers are computed using age-specific rates and corresponding populations for 10 age-groups. GLOBOCAN 2012 (IARC) - 25.2.2015: Mortality: Egypt
  9. 9. Estimated numbers (thousands) Men Women Both sexes Cases Deaths 5-year prev. Cases Deaths 5-year prev. Cases Deaths 5-year prev. World 7410 4653 15296 6658 3548 17159 14068 8202 32455 More developed regions 3227 1592 8550 2827 1287 8274 6054 2878 16823 Less developed regions 4184 3062 6747 3831 2261 8885 8014 5323 15632 WHO Africa region (AFRO) 265 205 468 381 250 895 645 456 1363 WHO Americas region (PAHO) 1454 677 3843 1429 618 4115 2882 1295 7958 WHO East Mediterranean region (EMRO) 263 191 461 293 176 733 555 367 1194 WHO Europe region (EURO) 1970 1081 4791 1744 852 4910 3715 1933 9701 WHO South-East Asia region (SEARO) 816 616 1237 908 555 2041 1724 1171 3278 WHO Western Pacific region (WPRO) 2642 1882 4493 1902 1096 4464 4543 2978 8956 IARC membership (24 countries) 3689 1900 9193 3349 1570 9402 7038 3470 18595 United States of America 825 324 2402 779 293 2373 1604 617 4775 China 1823 1429 2496 1243 776 2549 3065 2206 5045 India 477 357 665 537 326 1126 1015 683 1790 European Union (EU-28) 1430 716 3693 1206 561 3464 2635 1276 7157 All Cancers (excluding non-melanoma skin cancer) Estimated Incidence, Mortality and Prevalence Worldwide in 2012
  10. 10. Estimated age- standardised rates (World) per 100,000 At a glance There were 14.1 million new cancer cases, 8.2 million cancer deaths and 32.6 million people living with cancer (within 5 years of diagnosis) in 2012 worldwide. 57% (8 million) of new cancer cases, 65% (5.3 million) of the cancer deaths and 48% (15.6 million) of the 5-year prevalent cancer cases occurred in the less developed regions. The overall age standardized cancer incidence rate is almost 25% higher in men than in women, with rates of 205 and 165 per 100,000, respectively. Male incidence rates vary almost five-fold across the different regions of the world, with rates ranging from 79 per 100,000 in Western Africa to 365 per 100,000 in Australia/New Zealand (with high rates of prostate cancer representing a significant driver of the latter). There is less variation in female incidence rates (almost three-fold) with rates ranging from 103 per 100,000 in South-Central Asia to 295 per 100,000 in Northern America. In terms of mortality, there is less regional variability than for incidence, the rates being 15% higher in more developed than in less developed regions in men, and 8% higher in women. In men, the rates is highest in Central and Eastern Europe (173 per 100,000) and lowest in Western Africa (69). In contrast, the highest rates in women are in Melanesia (119) and Eastern Africa (111), and the lowest in Central America (72) and South-Central (65) Asia. GLOBOCAN 2012 (IARC) , Section of Cancer Surveillance
  11. 11. Estimated Cancer Incidence Worldwide in 2012: Men  Estimated age-standardised rates (World) per 100,000
  12. 12. Trends in incidence of cancer in selected countries: age-standardised rate (W) per 100,000, men GLOBOCAN 2012 (IARC) , Section of Cancer Surveillance
  13. 13. Estimated Cancer Mortality Worldwide in 2012: Men 
  14. 14. GLOBOCAN 2012 (IARC) , Section of Cancer Surveillance (24/2/2015) Trends in mortality from cancer in selected countries: age-standardised rate (W) per 100,000, men
  15. 15. Estimated Cancer Incidence Worldwide in 2012: Women
  16. 16. GLOBOCAN 2012 (IARC) , Section of Cancer Surveillance (24/2/2015)
  17. 17. Estimated Cancer Mortality Worldwide in 2012: Women
  18. 18.   MORE DEVELOPED AREAS LESS DEVELOPED AREAS INCIDENCE MORTALITY INCIDENCE MORTALITY ASR CUMULATIVE  RISK (%)  ASR CUMULATIVE  RISK (%)  ASR CUMULATIVE  RISK (%)  ASR (%)   CUMULATIVE  RISK Males All cancers 300.1 30.1 143.9 15.0 160.3 17.0 119.3 12.7 Bladder 16.6 1.9 4.6 0.5 5.4 0.6 2.6 0.3 Brain, n. system 6.0 0.6 3.9 0.4 3.2 0.3 2.6 0.3 Colorectum 37.6 4.4 15.1 1.7 12.1 1.4 6.9 0.8 Esophagus 6.5 0.8 5.3 0.6 11.8 1.4 10.1 1.2 Gallbladder 2.4 0.3 1.6 0.2 1.4 0.2 1.1 0.1 H. lymphoma 2.2 0.2 0.4 0.0 0.9 0.1 0.6 0.1 Kidney 11.8 1.4 4.1 0.5 2.5 0.3 1.3 0.1 Larynx 5.5 0.7 2.4 0.3 3.5 0.4 2.1 0.3 Leukemia 9.1 0.9 4.8 0.5 4.5 0.4 3.7 0.3 Liver 8.1 1.0 7.2 0.9 18.9 2.2 17.4 2.0 Lung 47.4 5.7 39.4 4.7 27.8 3.3 24.6 2.9 Melanoma skin 9.5 1.0 1.8 0.2 0.7 0.1 0.3 0.0 Multi myeloma 3.3 0.4 1.9 0.2 0.9 0.1 0.8 0.1 Nasopharynx 0.6 0.1 0.3 0.0 2.1 0.2 1.4 0.2 N-H lymphoma 10.3 1.1 3.6 0.4 4.2 0.5 3.0 0.3 Oral cavity 6.9 0.8 2.3 0.3 4.6 0.5 2.7 0.3 Other pharynx 4.4 0.5 2.2 0.3 3.0 0.4 2.5 0.3 Pancreas 8.2 1.0 7.9 0.9 2.7 0.3 2.5 0.3 Prostate 62.0 7.8 10.6 0.9 12.0 1.4 5.6 0.5 Stomach 16.7 2.0 10.4 1.2 21.1 2.5 16.0 1.9 Testis 4.6 0.4 0.3 0.0 0.8 0.1 0.3 0.0
  19. 19. More developed                                             Females                                          less developed  All cancers 225.5 22.0 87.3 9.1 138.0 14.0 85.4 9.0 Bladder 3.6 0.4 1.0 0.1 1.4 0.2 0.7 0.1 Brain, n system 4.4 0.4 2.6 0.3 2.8 0.3 2.0 0.2 Breast 66.4 7.1 15.3 1.7 27.3 2.8 10.8 1.2 Cervix uteri 9.0 0.9 3.2 0.3 17.8 1.9 9.8 1.1 Colorectum 24.2 2.7 9.7 1.0 9.4 1.1 5.4 0.6 Corpus uteri 12.9 1.6 2.4 0.3 5.9 0.7 1.7 0.2 Esophagus 1.2 0.1 1.0 0.1 5.7 0.7 4.7 0.5 Gallbladder 2.1 0.2 1.5 0.2 2.2 0.3 1.7 0.2 H lymphoma 1.9 0.2 0.3 0.0 0.5 0.1 0.3 0.0 Kidney 5.8 0.7 1.7 0.2 1.4 0.2 0.8 0.1 Larynx 0.6 0.1 0.2 0.0 0.6 0.1 0.4 0.0 Leukemia 6.0 0.6 2.9 0.3 3.6 0.3 2.9 0.3 Liver 2.7 0.3 2.5 0.3 7.6 0.9 7.2 0.8 Lung 18.6 2.3 13.6 1.6 11.1 1.3 9.7 1.1 Melanoma skin 8.6 0.9 1.1 0.1 0.6 0.1 0.3 0.0 Multi myeloma 2.2 0.3 1.3 0.1 0.7 0.1 0.6 0.1 Nasopharynx 0.2 0.0 0.1 0.0 1.0 0.1 0.6 0.1 N-H lymphoma 7.0 0.8 2.2 0.2 2.8 0.3 1.9 0.2 Oral cavity 2.4 0.3 0.6 0.1 2.6 0.3 1.5 0.2 Other pharynx 0.8 0.1 0.3 0.0 0.8 0.1 0.6 0.1 Ovary 9.4 1.0 5.1 0.6 5.0 0.5 3.1 0.4 Pancreas 5.4 0.6 5.1 0.6 2.1 0.3 2.0 0.2 Stomach 7.3 0.8 4.7 0.5 10.0 1.1 8.1 0.9 Thyroid 9.1 0.9 0.4 0.0 3.4 0.4 0.7 0.1
  20. 20.   INCIDENCE MORTALITY   MALE FEMALE OVERALL MALE FEMALE OVERALL Eastern Africa 121.2 125.3 122.8 105.4 95.9 99.9 Middle Africa 88.1 96.7 91.8 78.5 75.6 76.4 Northern Africa 109.2 98.9 103.2 89.5 68.2 78.0 Southern Africa 235.9 161.0 189.6 172.1 108.1 133.2 Western Africa 92.0 123.5 107.6 80.1 91.2 85.4 Eastern Asia 222.1 158.1 188.4 155.5 87.3 120.1 South-Central Asia 99.7 110.8 104.6 78.0 71.7 74.5 South-Eastern Asia 143.9 141.7 141.5 112.3 89.4 99.5 Western Asia 152.8 119.5 133.8 113.9 74.3 92.2 Caribbean 196.3 153.5 172.6 116.6 86.2 99.9 Central America 136.2 134.4 134.4 84.7 80.6 82.0 Northern America 334.0 274.4 299.9 122.4 91.5 105.1 South America 186.7 162.9 171.9 116.6 88.2 100.3 C/Eastern Europe 259.2 184.2 210.6 181.5 94.0 128.1 Northern Europe 292.3 249.5 266.1 134.6 99.7 114.5 Southern Europe 289.9 212.2 245.0 149.9 81.2 111.7 Western Europe 337.4 250.9 287.7 138.4 84.3 108.0 Australia/New Zealand 356.8 276.4 313.3 125.6 86.0 104.1 Melanesia 146.0 133.4 138.5 119.8 95.9 106.8 Micronesia 153.8 164.4 157.5 104.7 70.3 86.1 Polynesia 225.0 201.5 209.8 133.6 87.9 109.1 Estimated Age-Standardized Incidence and Mortality Rates Per 100,000 by World Area, 2008
  21. 21. Cancer incidence and mortality by site and gender US 2014
  22. 22. CA: A Cancer Journal for Clinicians Volume 61, Issue 2, pages 69-90, 4 FEB 2011 DOI: 10.3322/caac.20107 http://onlinelibrary.wiley.com/doi/10.3322/caac.20107/full#fig2
  23. 23. Global burden of cancer 2008 • Based on the GLOBOCAN 2008 estimates, about 12.7 million cancer cases and 7.6 million cancer deaths are estimated to have occurred in 2008; of these, 56% of the cases and 64% of the deaths occurred in the economically developing world.
  24. 24. • Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among females (23% of the total cancer cases and 14% of the cancer deaths). • Lung cancer is the leading cancer site in males, comprising 17% of the total new cancer cases and 23% of the total cancer deaths. • Breast cancer is now the leading cause of cancer death among females in economically developing countries, a shift from the previous decade during which the most common cause of cancer death was cervical cancer. • The mortality burden for lung cancer among females in developing countries is as high as the burden for cervical cancer, with each accounting for 11% of the total female cancer deaths.
  25. 25. • Although overall cancer incidence rates in the developing world are half those seen in the developed world in both sexes, the overall cancer mortality rates are generally similar. • Cancer survival tends to be poorer in developing countries, most likely because of a combination of a late stage at diagnosis and limited access to timely and standard treatment. • A substantial proportion of the worldwide burden of cancer could be prevented through the application of existing cancer control knowledge and by implementing programs for tobacco control, vaccination (for liver and cervical cancers), and early detection and treatment, as well as public health campaigns promoting physical activity and a healthier dietary intake. CA Cancer J Clin 2011. © 2011 American Cancer Society, Inc.
  26. 26. Global cancer statistics: Age‐Standardized Breast Cancer Incidence and Mortality Rates by World Area CA: A Cancer Journal for Clinicians Volume 61, Issue 2, pages 69-90, 4 FEB 2011 DOI: 10.3322/caac.20107 http://onlinelibrary.wiley.com/doi/10.3322/caac.20107/full#fig4 Source: GLOBOCAN 2008.
  27. 27. Global cancer statistics: Age‐Standardized Colorectal Cancer Incidence Rates by Sex and World Area. CA: A Cancer Journal for Clinicians Volume 61, Issue 2, pages 69-90, 4 FEB 2011 DOI: 10.3322/caac.20107 http://onlinelibrary.wiley.com/doi/10.3322/caac.20107/full#fig5 Source: GLOBOCAN 2008.
  28. 28. Global cancer statistics: Age‐Standardized Lung Cancer Incidence Rates by Sex and World Area CA: A Cancer Journal for Clinicians Volume 61, Issue 2, pages 69-90, 4 FEB 2011 DOI: 10.3322/caac.20107 http://onlinelibrary.wiley.com/doi/10.3322/caac.20107/full#fig6 Source: GLOBOCAN 2008.
  29. 29. Global cancer statistics: Age‐Standardized Prostate Cancer Incidence and Mortality Rates by World Area CA: A Cancer Journal for Clinicians Volume 61, Issue 2, pages 69-90, 4 FEB 2011 DOI: 10.3322/caac.20107 http://onlinelibrary.wiley.com/doi/10.3322/caac.20107/full#fig7 Source: GLOBOCAN 2008.
  30. 30. Global cancer statistics: Age‐Standardized Stomach Cancer Incidence Rates by Sex and World Area CA: A Cancer Journal for Clinicians Volume 61, Issue 2, pages 69-90, 4 FEB 2011 DOI: 10.3322/caac.20107 http://onlinelibrary.wiley.com/doi/10.3322/caac.20107/full#fig8 Source: GLOBOCAN 2008.
  31. 31. Global cancer statistics: Age‐Standardized Cervical Cancer Incidence and Mortality Rates by World Area. CA: A Cancer Journal for Clinicians Volume 61, Issue 2, pages 69-90, 4 FEB 2011 DOI: 10.3322/caac.20107 http://onlinelibrary.wiley.com/doi/10.3322/caac.20107/full#fig11 Source: GLOBOCAN 2008.
  32. 32. Global cancer statistics: Age‐Standardized Liver Cancer Incidence Rates by Sex and World Area. CA: A Cancer Journal for Clinicians Volume 61, Issue 2, pages 69-90, 4 FEB 2011 DOI: 10.3322/caac.20107 http://onlinelibrary.wiley.com/doi/10.3322/caac.20107/full#fig9 Source: GLOBOCAN 2008
  33. 33. Global cancer statistics: Age‐Standardized Urinary Bladder Cancer Incidence Rates by Sex and World Area CA: A Cancer Journal for Clinicians Volume 61, Issue 2, pages 69-90, 4 FEB 2011 DOI: 10.3322/caac.20107 http://onlinelibrary.wiley.com/doi/10.3322/caac.20107/full#fig13 Source: GLOBOCAN 2008.
  34. 34. Global cancer statistics: Age‐Standardized Esophageal Cancer Incidence Rates by Sex and World Area CA: A Cancer Journal for Clinicians Volume 61, Issue 2, pages 69-90, 4 FEB 2011 DOI: 10.3322/caac.20107 http://onlinelibrary.wiley.com/doi/10.3322/caac.20107/full#fig12 Source: GLOBOCAN 2008.
  35. 35. Global cancer statistics: Age‐Standardized Non‐Hodgkin Lymphoma Incidence Rates by Sex and World Area CA: A Cancer Journal for Clinicians Volume 61, Issue 2, pages 69-90, 4 FEB 2011 DOI: 10.3322/caac.20107 http://onlinelibrary.wiley.com/doi/10.3322/caac.20107/full#fig14 Source: GLOBOCAN 2008.
  36. 36. Global cancer statistics: Age‐Standardized Oral Cavity Cancer Incidence Rates by Sex and World Area CA: A Cancer Journal for Clinicians Volume 61, Issue 2, pages 69-90, 4 FEB 2011 DOI: 10.3322/caac.20107 http://onlinelibrary.wiley.com/doi/10.3322/caac.20107/full#fig15 Source: GLOBOCAN 2008.
  37. 37. Global cancer statistics: Age‐Standardized Nasopharyngeal Cancer Incidence Rates by Sex and World Area CA: A Cancer Journal for Clinicians Volume 61, Issue 2, pages 69-90, 4 FEB 2011 DOI: 10.3322/caac.20107 http://onlinelibrary.wiley.com/doi/10.3322/caac.20107/full#fig16 Source: GLOBOCAN 2008.
  38. 38. The 10 Most Commonly Diagnosed Cancers: 2012 Estimates Total Number and Percentage of New Cases Diagnosed per Year, Worldwide
  39. 39. Global cancer statistics: Proportion of Infants Covered by National Infant Hepatitis B Immunization Programs, 2008 CA: A Cancer Journal for Clinicians Volume 61, Issue 2, pages 69-90, 4 FEB 2011 DOI: 10.3322/caac.20107 http://onlinelibrary.wiley.com/doi/10.3322/caac.20107/full#fig10 Source: World Health Organization/UNICEF coverage estimates, 1980 2008, July 2009.‐ *Includes some countries that have introduced hepatitis B in adolescent immunization schedules.
  40. 40. MYTH Cancer is a disease of developed countries FACT Low and middle-income countries now bear a majority share of the burden of cancer
  41. 41. Globocan 2008 Less Developed versus More Developed Countries Cancer IncidenceCancer Incidence Cancer DeathsCancer Deaths Less DevelopedLess Developed More DevelopedMore Developed More DevelopedMore Developed Less DevelopedLess Developed 4.8 million; 64%4.8 million; 64% 2.7 million; 37%2.7 million; 37% 7.1 million; 56%7.1 million; 56% 5.6 million; 44%5.6 million; 44%
  42. 42. Percent of Worldwide Cancers Diagnosed in Developing Countries • 1970 – 15% • 2008 – 56% • 2030 – 70% •Ferlay J, et al. GLOBOCAN 2008. Lyon: International Agency for Research on Cancer, 2010 •Beaulieu N, et al. Breakaway: the global burden of cancer—challenges and opportunities. A report from the Economist Intelligence Unit, 2009.
  43. 43. Most Common Cancer Site in Females Globally Source: GLOBOCAN 2008
  44. 44. Source: Knaul, Arreola, Mendez. estimates based on IHME, 2011. The Cancer Transition in Low and Middle Income Countries (LMICs): Breast and Cervical Cancer 53% 20%19% -31% 0% LMIC’s High income % Change in # of deaths 1980-2010- LMICs account for more than 90% and 60 % of cervical and breast cancers deaths respectively. - Both are leading killers – especially of young women.
  45. 45. Carcinogenesis
  46. 46. Carcinogenesis • Thetransformation of normal to neoplastic cellsiscaused by both endogenousand exogenousfactors, including chemical and physical agents, viruses, activation of cancer- promoting genes, and inhibition of cancer- suppressing genes.
  47. 47. Latency 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.
  48. 48. Multistage Carcinogenesis • Two stages: Initiation and Promotion. Theinitial two stagetheory based on the natural history of epidermal carcinogenesisin themousehaslasted for many years.
  49. 49. Stages of Carcinogenesis • 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.
  50. 50. Stages of Carcinogenesis • Promotion is induced by a stimulator of cell proliferation and enhances the carcinogenic process. A promoter, not carcinogenic in itself, enhancesother agents’ carcinogenicity. Theprogression in promotion processis reversibility and instability. Thestageof promotion can becontinually modulated by avariety of environmental alterations.
  51. 51. Multistage Carcinogenesis • 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.
  52. 52. Tumor Growth • 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
  53. 53. Human Cancer-Based Two-hit Model • 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 retinoblastoma, he suggested that one of the two mutations is already present at conception (germ-line mutation), and the second mutation occur as a somatic event (post conception).
  54. 54. Human Colon Cancer Multiple Stage Model • Colon cancer model. The development of human cancer is a multistage process, involving a series of genetic molecular alterations.
  55. 55. Early Stage versus Late Stage • “Early stage” versus “late stage” carcinogens in epidemiologic stages. - If an agent is “early stage” carcinogen, 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.
  56. 56. Early Stage versus Late Stage
  57. 57. Molecular Genetic of Cancer • 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 germ- line of persons with hereditary predisposition to a variety of cancers
  58. 58. • 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 MOLECULAR GENETIC OF CANCER
  59. 59. DNA endogenous damage and Repair • Approximately 20,000 DNA damage lesions/cell/day • 1 billion DNA damage lesions/human body/second Lindahl T, Quart Biol 2000,65,127-33
  60. 60. Genetic Mutations and Tumor 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.
  61. 61. Cell Transformation • 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
  62. 62. Transformed cells share common attributes o Autonomous generation of mitogenic signals o Insensitivity to exogenous antigrowth signal o Resistance to apoptosis o Limitless replicative potential (immortalization) o Blocked differentiation o Ability to sustain angiogenesis o Capacity to invade surrounding tissues o Potential to metastasize
  63. 63. Oncogenes • Oncogenesarealtered version of normal genes, termed protooncogene, that regulate normal cell growth, differentiation, and survival • Gain-of-function (dominant) mutations activateprotooncogenesto become oncogenesand arepositiveeffectorsof the neoplastic phenotype
  64. 64. Mechanisms of Oncogene Action • Growth factors(IGF-1) • Cell surfacereceptors • Intracellular signal transduction pathways • DNA-binding nuclear protein (transcription factors) • Cell cycleproteins(cyclinsand cyclin- dependent protein kinases) • Inhibitorsof apoptosis(bcl-2)
  65. 65. Tumor Suppressor Genes • 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
  66. 66. TumorSuppressorGenes • 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.
  67. 67. Carcinogens An agent that can causecancer. The International Agency for Research on Cancer (IARC) classifiescarcinogensasfollows: • 1) Sufficient evidence. A positive causal relationship has been established between exposure and occurrence of cancer.
  68. 68. Carcinogens • 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.
  69. 69. Carcinogens • 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.  
  70. 70. Carcinogens • 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.
  71. 71. Overall evaluation of carcinogen Taking all theevidenceinto account, theagent isassigned to oneof the following categories: Group 1. Theagent iscarcinogenic to humans. Group 2. 2A. Theevidencefor human carcinogenicity isalmost sufficient (probably carcinogenic). 2B. Thereareno human databut thereisexperimental evidenceof carcinogenicity (possibly carcinogenic). Group 3. Theagent isnot classifiableasto itshuman carcinogenicity. Group 4. Theagent isprobably not carcinogenic to humans.
  72. 72. Classification of carcinogenic Agents in Relation to Their Action on One or More Stages of Carcinogenesis
  73. 73. Group 1: Carcinogenic to Humans • Tobacco Smoking • Tobacco Products, Smokeless • 4-Aminobiphenyl (4-ABP) • Benzene • Cadmium • Chromium • 2-Naphthylamine (2-NA) • Nickel • Polonium-210 (Radon) • Vinyl Chloride
  74. 74. Group 2A: Probably Carcinogenic to Humans • Acrylonitrile • Benzo[a]pyrene • Benzo[a]anthracene • 1,3-Butadiene • Dibenz(a,h)anthracene • Formaldehyde • N-Nitrosodiethylamine • N-Nitrosodimethylamine
  75. 75. Group 2B: Possibly Carcinogenic to Humans • Acetaldehyde • Benzo[b]fluoranthene • Benzo[j]fluoranthene • Benzo[k] fluoranthene • Dibenz[a,h]acridine • Dibenz[a,j]acridine • 7H-Dibenz[c,g]carbazole
  76. 76. Group 2B: Possibly Carcinogenic to Humans • Dibenzo(a,i)pyrene • Dibenzo(a,l)pyrene • 1,1-Dimethylhydrazine • Hydrazine • Indeno[1,2,3-cd]pyrene • Lead • 5-methylchrysene
  77. 77. Group 2B: Possibly Carcinogenic to Humans • 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) • 2-Nitropopane • N-Nitrosodiethanolamine • N-Nitrosomethylethylamine • N-Nitrosomorpholine • N-Nitrosonornicotine (NNN) • N-Nitrosopyrrolidine
  78. 78. Group 2B: Possibly Carcinogenic to Humans • Quinoline • ortho-Toluidine • Urethane (Ethyl Carbamate)
  79. 79. Group 3: Unclassifiable as to Carcinogenicity to Humans (Limited Evidence) • Chrysene • Crotonaldehyde • N-Nitrosoanabasine (NAB) • N-Nitrosoanatabine (NAT)
  80. 80. 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 mEHNQO1 XRCC1 GSTM 1 Background: Theoretical model of gene-gene/environmental interaction pathway Ile105 Val ↓ Ala114 Val↓ Tyr113 His↓ His139 Arg↑ Tyr113 His↓ His139Arg↑ Pro187 Ser↓ MspI Ile462 Val ↑ Arg194 Trp, Arg399Gln, Arg280 His↓ Null ↓ Ala146Thr Arg72 Pro↓ G870 A↑
  81. 81. Chemical/environmental carcinogens • Smoking and lung cancer • Sun exposure and squamous cell carcinoma of skin • Asbestos exposure and lung cancer • Smoked 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
  82. 82. Radiation • 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
  83. 83. Viral 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
  84. 84. Precursors • Isacondition which beassociated with the development of cancer (Stout, 1932) • Visiblestepsin adynamic processof neoplasiathat may or may not undergo progression to amoreadvanced stageof neoplasia(Foulds, 1958) • All morphologic lesionson thepathway from normal tissueto cancer, up to but not including invasivecancer
  85. 85. Precursors 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
  86. 86. Significance • 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 insight into the nature of carcinogenesis
  87. 87. Thank you

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