Etiology of Cancer

Comprehensive seminar on etiology of cancer from Devita

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

4. Indian ICMR Data

5. 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%)

6. A. TOBACCO

7. 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

8. 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

9. Mechanism of Tobacco Carcinogenesis

10. 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

11. B. Cancer Susceptibility Syndromes

12. 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.

13. 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.

14. 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

15. 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

16. 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

17. C. Dna Viruses & RNA Viruses

18. DNA Viruses Hepadnaviruses Papillomaviruses Epstein-Barr Virus Kaposi’s Sarsoma – Associated Herpesvirus Human Polyomaviruses

19. RNA Viruses Retroviruses HTLV -1 HTLV -2 Human Immunodeficiency Virus Hepatitis C Virus

20. 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

21. D. INFLAMMATION

22. 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.

23. 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

24. 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

25. Tissue damage and repair . Increase in the proliferation rate in the affected tissue. Increase in the probability of mutation or chromosomal translocation during mitosis.

26. E. Chemical Factors

27. 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

28. F. Physical Factors

29. Ionizing radiation Ultraviolet Radiation RF & Microwave Radiation Electromagnetic Fields Asbestos Nanoparticles

30. Hiroshima and Nagasaki Bombings Chernobyl Accident

31. 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.

32. 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.

33. G. Dietary Factors

34. 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.

35. 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.

36. 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.

37. 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.

38. 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.

39. H. Obesity & Physical Activity

40. 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.

41. 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..

42. 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.

43. THANK YOU Who is the one Smoking?

44. References Devita Hellman and Rosenberg’s Cancer: Principles and Practice of Oncology, 9 th Edition. Wikipedia Google Images