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Etiology of Cancer: Understanding the Causes
- 1. ETIOLOGY OF CANCER Dr. Abhilash G JR-1 Radiotherapy SRMSIMS
- 2. 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.
- 3. 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
- 6. 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 (30-35%)
- 7. A. TOBACCO
- 8. 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
- 10. 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
- 11. MECHANISM OF TOBACCO CARCINOGENESIS
- 12. CARCINOGENS AND TOBACCO-INDUCED CANCERS Lung 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
- 14. 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.
- 15. 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.
- 16. CANCER SUSCEPTIBILITY GENES & ASSOCIATED SYNDROMES Function 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
- 17. 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
- 18. 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
- 19. C. DNA VIRUSES & RNA VIRUSES
- 20. DNA VIRUSES Hepadnaviruses Papillomaviruses Epstein-Barr Virus Kaposi’s Sarsoma – Associated Herpesvirus Human Polyomaviruses
- 21. RNA VIRUSES Retroviruses HTLV -1 HTLV -2 Human Immunodeficiency Virus Hepatitis C Virus
- 22. HUMAN VIRUSES WITH ONCOGENIC PROPERTIES Virus 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
- 23. D. INFLAMMATION
- 24. 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.
- 25. 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
- 26. 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
- 27. Tissue damage and repair . Increase in the proliferation rate in the affected tissue. Increase in the probability of mutation or chromosomal translocation during mitosis.
- 29. 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
- 31. Ionizing radiation Ultraviolet Radiation RF & Microwave Radiation Electromagnetic Fields Asbestos Nanoparticles
- 33. 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.
- 35. 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.
- 38. 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.
- 39. 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.
- 40. 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.
- 41. 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.
- 42. 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.
- 43. H. OBESITY & PHYSICAL ACTIVITY
- 44. 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
- 46. 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..
- 47. 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.
- 48. Who is the one
- 49. REFERENCES Devita Hellman and Rosenberg’s Cancer: Principles and Practice of Oncology, 9th Edition. Wikipedia Google Images
Editor's Notes
- Good Evening Everybody.. I’m Dr. Abhilash from Dept of Radiotherapy.. My topic for today is Etiology of Cancer..
- US cancer researchers Douglas Hanahan and Robert Weinberg Prof Weinberg also discovered the first human oncogene Ras and the first tumor supressor gene Rb..
- Estimated 12.7 million cancer cases around the world in 2008 ( GLOBOCAN) and 7.6 million cancer deaths in 2008. Number expected to be 21 million in 2030..
- Panel A - represents the rare occurrence of a highly penetrant inherited gene mutation, such as in the adenomatous polyposis coli (APC) gene, which confers a 100% likelihood of cancer of the colon, regardless of environment Panel B - represents the vast majority of cancers, in which carcinogenesis is driven by gene/environment interaction, is represented. Panel C - represents the rare occurrence of an overwhelmingly carcinogenic exposure, such a radiation accidents, will lead to cancer in exposed individuals regardless of genetic background.
- The three most common childhood cancers are leukemia (34%), brain tumors (23%), and lymphomas (12%)
- DNA adducts – Covalent bonds between carcinogens and DNA; cause miscoding and permanent mutation in critical genes
- DNA adducts – Covalent bonds between carcinogens and DNA; cause miscoding and permanent mutation in critical genes
- There is, however, no evidence to suggest that HIV is directly oncogenic. In HIV-infected persons, non-Hodgkin lymphoma (Burkitt, immunoblastic, and primary CNS), Kaposi sarcoma, and cervical cancer are all AIDS-defining illnesses. In addition, anal squamous cell carcinoma is commonly seen in AIDS patients. Many of the neoplasms common to AIDS patients are associated with infection by DNA viruses. These viruses include Kaposi sarcoma-associated herpesvirus/human herpes virus-8, Epstein-Barr virus, and human papilloma virus.
- On August 6, 1945 the uranium bomb, “Little Boy”, was dropped on Hiroshima killing 70,000-80,000 people immediately. Three days later, the plutonium bomb, “Fat Man”, was dropped on Nagasaki killing an estimated 40,000-75,000 instantly. Catastrophic nuclear accident that occurred on 26 April 1986 at the Chernobyl Nuclear Power Plant in Ukraine.. An explosion and fire released large quantities of radioactive particles into the atmosphere, which spread over much of the western USSR and Europe.
- Specific Activity Rate (SAR) is a measure of the rate at which energy is absorbed by the body when exposed to a radio frequency (RF) electromagnetic field.