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

1. Cancer Epidemiology I
Professor Tarek Tawfik Amin
amin55@myway.com

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. Biologic Basis
Normal
cell
Initiated
cell
Pre-cancerous
cell
CANCER
Initiation Promotion Progression

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. 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. http://www.globocan.iarc.fr
assessing the cancer burden (incidence-
mortality)

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. 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. 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

11. 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

12. Estimated Cancer Incidence Worldwide in 2012: Men
Estimated age-standardised rates (World) per 100,000

13. Trends in incidence of cancer in selected countries: age-standardised rate (W) per
100,000, men
GLOBOCAN 2012 (IARC) , Section of Cancer Surveillance

16. Estimated Cancer Mortality Worldwide in 2012: Men

17. 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

20. Estimated Cancer Incidence Worldwide in
2012: Women

22. GLOBOCAN 2012 (IARC) , Section of Cancer Surveillance (24/2/2015)

25. Estimated Cancer Mortality Worldwide in
2012: Women

30.
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

31. 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

32. 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

33. Cancer incidence and mortality by site and gender US 2014

34. 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

35. 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.

36. • 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.

37. • 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.

38. 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.

39. 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.

40. 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.

41. 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.

42. 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.

43. 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.

44. 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

45. 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.

46. 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.

47. 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.

48. 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.

49. 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.

50. The 10 Most Commonly Diagnosed Cancers: 2012 Estimates
Total Number and Percentage of New Cases Diagnosed per Year, Worldwide

51. 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.

52. MYTH
Cancer is a disease of developed
countries
FACT
Low and middle-income countries
now bear a majority share of the
burden of cancer

53. 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%

54. 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.

55. Most Common Cancer Site in Females Globally
Source: GLOBOCAN 2008

56. 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.

57. Carcinogenesis

58. 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.

59. 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.

62. Multistage Carcinogenesis
• Two stages: Initiation and Promotion.
Theinitial two stagetheory based on the
natural history of epidermal carcinogenesisin
themousehaslasted for many years.

63. 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.

64. 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.

66. 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.

68. 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

69. 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).

71. 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.

72. 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.

73. Early Stage versus Late Stage

75. 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

76. • 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

77. 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

78. 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.

79. 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

80. 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

81. 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

82. 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)

83. 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

84. 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.

86. 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.

87. 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.

88. 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.

89. 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.

90. 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.

91. Classification of carcinogenic Agents in Relation to Their
Action on One or More Stages of Carcinogenesis

92. 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

93. 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

94. 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

95. 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

96. 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

97. Group 2B: Possibly Carcinogenic to Humans
• Quinoline
• ortho-Toluidine
• Urethane (Ethyl Carbamate)

98. Group 3: Unclassifiable as to Carcinogenicity to Humans
(Limited Evidence)
• Chrysene
• Crotonaldehyde
• N-Nitrosoanabasine (NAB)
• N-Nitrosoanatabine (NAT)

99. 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↑

100. 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

101. 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

103. 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

105. 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

106. 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

107. 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

108. Thank you