Risk Factors in Human Carcinogenesis PDF

Risk Factors in Human Carcinogenesis 1- Life style Factors 2- Carcinogenic agents 3- Age 4- Hereditary factors 5- Pre-neoplastic conditions  1- Lifestyle factors Reproductive Environment Diet Smoking...

Risk Factors in Human Carcinogenesis 1- Life style Factors 2- Carcinogenic agents 3- Age 4- Hereditary factors 5- Pre-neoplastic conditions  1- Lifestyle factors Reproductive Environment Diet Smoking life Exposure to carcinogens, hormonal modifications influenced by childbirth and birth control, and exposure to viruses, underlie these lifestyle factors. Epidemiology has been instrumental in elucidating the contributions of these factors towards different cancers. 1-Life Style Factors 1. Environment Unprotected exposure to sun (UV radiation) alter chimney sweeps  nasal DNA  Skin Cancer cancer 2. Reproductive life having children reduces breast cancer risk for women compared with not having children. The age of a woman at the time of giving birth for the first time and the age of a woman at the initiation and termination of her menstrual cycles also influences cancer risk. 3. Diet 3. Diet: Stomach cancer is a predominant cancer in the Japanese population and a minor cancer in the population of the USA. The risk of stomach cancer in Japanese people who have migrated to the USA decreases only if they adopt the American diet, but not if they retain a Japanese diet. The Mediterranean diet, which is rich in fresh fruit and vegetables, has been promoted to be beneficial in reducing cancer risks. 4. Alcohol Alcohol was classified as a carcinogen by the International Agency for Research on Cancer in 2007.  5. Smoking Smoking accounts for 40% of all cancer deaths: 1.18 million deaths. At least 81 carcinogens have been identified in cigarette smoke. More than 30% of cancer deaths could be prevented by modifying or avoiding key risk factors 6. Additional Influences By-products of our metabolism and errors that occur during DNA replication contribute to carcinogenesis Aerobic metabolism produces by-products of oxygen radicals that are mutagenic During DNA replication and repair, polymerases can introduce mutations directly in DNA because of their associated error rates. 2- Carcinogenic Agents 1. Radiation 2. Chemicals 3. Infectious pathogens 4. Endogenous carcinogenic reactions  1. Radiation Energy waves Atomic particles 1. Gamma (γ) rays 1. alpha (α) 2. Electromagnetic radiation (similar 2. beta (β) particles to x-rays) Several types of radiation (including both energy waves and atomic particles) can damage DNA and act as carcinogens. Two classes of radiation, ionizing radiation and UV radiation, have been demonstrated to act as carcinogens and damage DNA. 1.1 Ionizing radiation Includes both alpha and beta particles (atomic particles) and gamma rays (energy waves) Induces ionization of molecules Can damage DNA directly by causing ionization of the atoms comprising DNA, or indirectly by the interaction with water molecules to generate dangerous reactive oxygen species (ROS) Evidence suggests that the most important damage associated with ionizing radiation-induced carcinogenesis is double-strand DNA breaks. 1.2 Ultraviolet radiation Principle cause of skin cancer UVB is the most effective carcinogen The conjugated double bonds in the rings of the nitrogenous bases of DNA absorb UV radiation  dimers  transitions UVA indirectly damages DNA via free radical-mediated damage Water is fragmented by UVA, generating electron-seeking ROS (such the hydroxyl radical as mentioned earlier) that cause DNA damage 2. Chemical Carcinogens Many chemicals in our environment and in our diet play a role in human carcinogenesis. Cytochrome P450 enzymes family is involved in the metabolism of chemicals in the liver and is important in the activation of carcinogens to ultimate carcinogens. Examples 1. polycyclic aromatic hydrocarbons (PAHs) 2. aromatic amines 3. nitrosamines and nitrosamides  Fibrous Minerals: Asbestos And Erionite Naturally occurring fibrous minerals that act as chemical/physical carcinogens and mutagens Asbestos is a group of fibrous silicate minerals that was used extensively in building materials because of its insulating properties but is now prohibited in several countries Occupational cancers, Chemical Carcinogens Beryllium, chromium, radon, nickel---lung cancer Arsenic compounds---lung, skin,hemangiosarcoma Benzene---leukemia, Hodgkin’s lymphoma Asbestos---- lung, mesothelioma, GI cancers (esophagus, stomach, large bowel) Cadmium---- Prostate  3. Infectious Pathogens As Carcinogens Early in the 20th century, viruses were shown to cause tumors in animals Oncogenic viruses DNA tumor viruses RNA tumor viruses Encode viral proteins that block (Retroviruses) tumor suppressor genes, often by Encode mutated forms of normal genes (i.e. Oncogenes) that have a protein–protein interactions dominant effect in host cells Some DNA viruses replicate Replicate by integration of the viral strictly as episomes within host genome into the host DNA and utilize the host’s translational machinery to cells produce viral proteins Examples of carcinogenic pathogens Pathogen Associated cancer Human papillomavirus (type 16 and 18) Cervical cancer Kaposi’s sarcoma-associated herpesvirus Kaposi’s sarcoma (KSHV) Hepatitis B virus Liver cancer Epstein–barr virus (EBV) Nasopharyngeal carcinoma Human t-cell lymphotropic virus type 1 T-cell leukemia (HTLV-1) Helicobacter pylori Gastric cancer S. Typhi Hepatobiliary and gallbladder carcinoma  Viruses associated with human neoplasms Human Hepatitis B Epstein Barr Human T-cell papilloma and C virus virus (EBV) Leukemia virus virus Hepatocellular Cervical Burkitt's T-cell carcinoma cancers lymphoma Leukemia Nasopharyngeal carcinoma Hodgkins lymphoma Lymphoma in immuno- suppressed  4. Endogenous Carcinogenic Reactions Endogenous cellular reactions generate mutations Oxidative respiration and lipid peroxidation produce ROS that can react with DNA and lipids to produce oxidized products Spontaneous chemical reactions (e.g. hydrolysis of the glycosidic bond between a base and deoxyribose producing an abasic site) also contribute to the formation of mutations Errors during DNA replication and DNA recombination contribute to the formation of mutations  3- Age ◦ Frequency of cancers increases with age (55-74 years), due to accumulation of somatic mutations. ◦ Children are affected by certain neoplasms, e.g.: Lymphoblastic Leukemia and lymphoma Neoplasms of CNS Retinoblastoma- retina Soft tissue sarcoma Bone sarcomas 25  4- Heriditary Cancers ◦ Constitutes about 5-10% of all human cancers. ◦ Hereditary cancers tend to be bilateral and arise earlier in life. 26  4- Heriditary Cancers ◦ Hereditary forms of cancer can be divided into three categories 1. Autosomal dominant cancer syndromes 2. Autosomal recessive syndromes 3. Familial cancers 27 Hereditary Cancers Autosomal dominant cancer syndromes:  Inheritance of a single mutant gene increases risk of developing a tumor  Arise in preexisting lesions:  Retinoblastoma; 60% have defective tumor suppressor gene  Familial adenomatous polyposis; 100% develop colon cancer age 50 Autosomal recessive cancer syndromes:  Characterized by chromosomal or DNA instability  Xeroderma pigmentosum; defective DNA repair Familial cancers of uncertain inheritance:  Evidence of familial clustering, but transmission pattern is not clear  Cancers of colon, breast, ovary and brain  Tumors occur at an early age, arise in two or more close relatives, and sometimes multiple or bilateral  Familial cancers do not arise in preexisting lesions  5- Aquired pre-neoplastic conditions Some non-neoplastic lesions increase the likelihood for development of cancer, however most do not progress to cancer (pre-cancerous conditions) Examples include: Squamous metaplasia and dysplasia of bronchi in smokers- risk for lung cancer Endometrial hyperplasia and dysplasia in women with estrogenic stimulation- risk for endometrial cancer Villous adenoma of colon- risk for colorectal carcinoma Leukoplakia of the oral cavity and vulva, risk for squamous cell Ca