Etiology of Cancer
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Transcript of Etiology of Cancer
ETIOLOGY OF CANCER
Dr. Abhilash G
JR-1 Radiotherapy
SRMSIMS
WHAT IS CANCER?
Cancer, known medically as a malignant neoplasm, is a broad group of various diseases, all involving unregulated cell growth.
In cancer, cells divide and grow uncontrollably forming malignant tumors and invade nearby parts of the body.
The cancer may also spread to more distant parts through lymph or blood.
HANAHAN’S SIX HALLMARKS OF CANCER
Self Sufficiency in Growth Signals
Insensitivity to Antigrowth Signals
Tissue Invasion and Metastasis
Limitless Replicative Potential
Sustained Angiogenesis
Evading Apoptosis
Prof. Douglas
Hanahan
Prof. Robert
Weinberg
Indian ICMR Data
ROAD MAP FOR DISCUSSION
A. Tobacco (25-30%)
B. Cancer Susceptibility Syndrome (5-
10%)
C. DNA Viruses & RNA Viruses
D. Inflammation (15-
20%)
E. Chemical Factors
F. Physical Factors (up to 10%)
G. Dietary Factors
H. Obesity and Physical Activity
(30-35%)
A. TOBACCO
There are about 1.2 billion smokers and
hundreds of millions of smokeless tobacco
users.
Cigarette smoking causes well over 1 million
cancer deaths worldwide.
Lung Cancer is the dominant malignancy.
19 cancers for which evidence is considered
sufficient that they are caused by cigarette
smoking
3 cancers caused by smokeless tobacco
CONSTITUENTS OF CIGARETTE SMOKE CLASSIFIED BY IARC AS
CARCINOGENIC ( UPDATED AND REVISED IN 2010)
72 compounds listed and 15 are carcinogenic to
humans
Polycyclic Aromatic Hydrocarbons
N-Nitrosamines
Aromatic Amines
Aldehydes
Phenolic Compounds
Nitrohydrocarbons
Miscellaneous Organic Compounds
Metals and Inorganic Compounds
MECHANISM OF TOBACCO CARCINOGENESIS
CARCINOGENS AND TOBACCO-INDUCED
CANCERSLung PAH, NNK, Isoprene, Aldehydes,
Benzene
Larynx PAH
Nasal NNK, NNN
Oral Cavity PAH, NNK, NNN
Esophagus NNN, Other Nitrosamines
Liver NNK, Other Nitrosamines
Pancreas NNK, NNAL
Cervix PAH, NNK
Bladder Aromatic Amines
Leukemia Benzene
Colorectal Heterocyclic Aromatic Amines
PAH – Polyaromatic Hydrocarbons ; Nitrosamines - NNN, NNK, NNAL
B. CANCER
SUSCEPTIBILITY
SYNDROMES
Some genetic mutations confer such pro-
tumorigenic power that individuals who harbour
them are at extreme risk for cancer development.
A large number of proteins that regulate genomic
integrity (caretakers) and critical tumour suppressors
are mutated in cancer susceptibility syndromes.
Hereditary tumorigenesis - One mutant allele is inherited from either parent
Sporadic tumorigenesis - One allele is mutated somatically, in which case there is one
predisposed cell.
CANCER SUSCEPTIBILITY GENES &
ASSOCIATED SYNDROMESFunction Gene Associated
Syndrome
Regulation of Translation PTEN
LKB1
Cowden Syndrome
Peutz-Jeghers
Syndrome
PTCH 1
Nevoid Basal Cell
Syndrome
Regulation of
Proliferation NF 1 Neurofibromatosis 1
(AD)
APC Familial Adenomatous
Polyposis (AD)
Genomic Integrity and
Apoptosis BLM Bloom’s Syndrome
TP53 Li-Fraumeni Syndrome
PREVALENT SYNDROMES
HNPCC/ Lynch Syndrome – Most common CS
disease; Incidence is 1 in 400; AD with 90%
penetrance; Additional Risk of Endometrial
Cancer.
Hereditary Breast-Ovarian Cancer Syndrome
(HBOC) – BRCA 1 and BRCA 2 mutations; AD
with 85% penetrance.
NF 1 – AD with 100% penetreance.
FAP – AD with high penetrance; Germ line
mutation in APC gene on 5q
CS SYNDROMES DUE TO PROTO-
ONCOGENE ACTIVATION
Costello Syndrome – HRAS Gene
Hereditary Papillary Renal Cancer – MET Gene
Multiple Endocrine Neoplasia Type 2 – RET Gene
Hereditary Gastrointestinal Stromal Tumors – KIT
Gene
Familial Melanoma – CDK4 Gene
C. DNA VIRUSES & RNA
VIRUSES
DNA VIRUSES
Hepadnaviruses
Papillomaviruses
Epstein-Barr Virus
Kaposi’s Sarsoma – Associated
Herpesvirus
Human Polyomaviruses
RNA VIRUSES
Retroviruses
HTLV -1
HTLV -2
Human Immunodeficiency Virus
Hepatitis C Virus
HUMAN VIRUSES WITH ONCOGENIC
PROPERTIESVirus Family Type Assoc Tumors Cofactors
Flaviviruses Hepatitis C Hepatocellular Ca -
Hepadnavirus Hepatitis B Hepatocellular Ca Aflatoxin, Alcohol,
Smoking
Herpesviruses EBV Burkitt’s Lymphoma,
Nasopharyngeal
Carcinoma, HL,
Gastric Cancers
Malaria
Nitrosamines
KSHV(HSV8)
Kaposi’s Sarcoma,
Pulmonary Effusion
Lymphoma,
Castleman’s Disease
HIV Infection
Papillomaviruses HPV 16,18 Anogenital Cancers Smoking
Polyomaviruses Merkel Cell
Virus
Merkel Cell
Carcinoma
Immunosuppression
Retroviruses HTLV-1 Adult T Cell
Leukemia
Uncertain
D. INFLAMMATION
CANCER AND INFLAMMATION
Chronic inflammation tends to be associated with protumor effects.
Acute inflammation is associated with an antitumor effect.
However, this distinction is not absolute.
CHRONIC INFLAMMATORY CONDITIONS
ASSOCIATED WITH TUMOR FORMATION
Pathological Condition Associated Tumors Etiological Agent
Sjogren Syndrome,
Hashimoto’s Thyroiditis
Mucosa-assoc lymphoid
tissue lymphomas
-
Reflux esophagitis,
Barrett’s esophagus
Esophageal Carcinoma Gastric acid, Alcoholism,
Smoking
Liver Cirrhosis Hepatocellular Carcinoma Alcoholism
IBD Colorectal carcinoma -
Cystitis, Bladder Bladder Carcinoma Chronic indwelling, urinary
inflammation catheters
Asbestosis, Silicosis Mesothelioma, Lung
Carcinoma
Asbestos fibres, Silica
particles
CANCERS ASSOC WITH INFLAMMATION CAUSED
BY INFECTIOUS AGENTS
Pathological Condition Associated Tumor Pathogens
Hepatitis HCC Hepatitis B, C
Mononucleosis B cell NHL and Burkitt’s EBV
AIDS NHL, SCC, KS HIV, HHV-8
Warts Skin cancer Papillomaviruses
Gastritis/Ulcers Gastric adenocarcinoma H.Pylori
Chronic Cholecystitis Gall bladder Cancer Bacteria, Gallbladder
Stones
Opisthorchiasis, Cholangitis Cholangiosarcoma, Colon Ca Opisthorchis viverrini,
Opisthorcis sinensis
Chronic Cystitis Bladder, Liver, Rectal Ca,
Follicular lymphoma of
Spleen
S.hematobium,
S.japonicum, Irradiation,
Carcinogens
Tissue damage and repair .
Increase in the proliferation rate in the affected tissue.
Increase in the probability of mutation or chromosomal translocation during
mitosis.
E. CHEMICAL FACTORS
CHEMICAL CARCINOGENS
Lung & Pleura Tobacco, Arsenic,
Asbestos, Silica, Coal tar
Aluminum production, coal
gasification, coke
production, hematite
mining, painters,
Oral Cavity Tobacco, Alcoholic, nickel
compounds
Boot and shoe production,
Furniture manufacturer
Gastric Smoked, salted and
pickled foods
-
Colon Heterocyclic amines,
Asbestos
Pattern Makers
Liver Aflatoxin, vinyl chloride,
alcoholic beverages -
Bladder Tobacco smoke, Benzidine,
Phenacetin
Magenta manufacture,
auramine manufacture
F. PHYSICAL FACTORS
Ionizing radiation
Ultraviolet Radiation
RF & Microwave Radiation
Electromagnetic Fields
Asbestos
Nanoparticles
Hiroshima and Nagasaki
Bombings
Chernobyl
Accident
It has been estimated that 1 Gy of ionizing radiation
gives rise to about 40 DSBs, 1,000 SSBs, 1,000
base lesions, and 150 DNA-protein cross-links per
cell.
RFR and MR do not have sufficient energies to
cause ionizations in target tissues.
Sources - mobile phones, radars, medical devices,
and kitchen appliances.
Mobile phones emit radiofrequency radiation (RFR)
and generate EMFs.
At these intensities, induction of DNA damage has
been detected only in laboratory studies.
G. DIETARY FACTORS
DIET
Mutagens in foods, due to heating of
proteins, can cause damage to DNA.
Alcohol - Best established dietary risk factor
Fat – Cancers of breast, colon, prostate, and
endometrium.
Red meat - Increased risk of colorectal
cancer.
Direct damage in the upper GI tract.
Modulation of DNA methylation.
Acetaldehyde - Enhances proliferation of epithelial cells,
forms DNA adducts, and is a recognized carcinogen.
CONTD..
Regular consumption - Increased risk of colorectal cancer.
The association is strongest for processed meat.
Anabolic hormones used in meat production.
Heterocyclic amines and PAH formed during cooking.
High amounts of heme iron, and nitrates and related
compounds convert to carcinogenic nitrosamines in the
colon.
CONTD..
Fruits and vegetables have been hypothesized in
cancer prevention.
Contain antioxidants, minerals, fiber, potassium,
carotenoids, vitamin C, folate, and other vitamins.
Supply less than 5% of total energy intake but
concentration of micronutrients in these foods is
greater than in most others.
CONTD..
Fiber is fermented by the luminal bacteria of the colon.
Bulking effect ; Reduces colonic transit time, and the binding
of potentially carcinogenic luminal chemicals.
May also aid in producing short-chain fatty acids that may
be directly anticarcinogenic, and fiber may induce apoptosis.
H. OBESITY &
PHYSICAL ACTIVITY
Overweight Endogenous Risk of
Endometrial
& Obesity estrogen levels & Breast Cancer
Established risk factor for colon cancer in both men and
women.
Increased physical activity - Protective for colon cancer.
Impact on insulin sensitivity and IGF profiles, and
inflammation, as well as some colon-specific mechanisms
Physical activity stimulates stool transit in the colon,
decreasing the exposure of colonic mucosa to carcinogens in
the stool.
CONTD..
Obese & Gastro esophageal Gastric
High BMI Reflux symptoms
Adenocarcinoma
Obesity, in addition to high blood pressure and diabetes, is
an established risk factor for kidney cancer.
High BMI and Obesity have also been implicated in various
studies of Gall Bladder Cancer, Pancreatic Cancer, Prostate
Cancer and NHL..
TAKE HOME MESSAGE
Most common causes of cancer are Tobacco(25-
30%), Diet and Physical Activity related Factors
(30-35%).
60-65% cancers can be prevented just by Lifestyle
modification.
Vaccines which can prevent malignancies should
be emphasized and counseled to parents.
Genetically related malignancies like Breast and
Colon Cancer should have screening and Genetic
Counseling.
Who is the one
Smoking?
REFERENCES
Devita Hellman and Rosenberg’s Cancer:
Principles and Practice of Oncology, 9th
Edition.
Wikipedia
Google Images