Lecture 18

Risk Factors in Human Carcinogenesis

Lifestyle Factors

• Exposure to carcinogens, hormonal modifications, and exposure to viruses influence reproductive life, diet, and environment
• Unprotected exposure to UV radiation alters DNA, leading to skin cancer
• Having children reduces breast cancer risk for women compared to not having children
• Age of first birth and menstrual cycles influence cancer risk
• Stomach cancer is prevalent in Japan, but risk decreases if Japanese people adopt an American diet
• The Mediterranean diet, rich in fruits and vegetables, is beneficial in reducing cancer risks
• Alcohol is a carcinogen, classified by the International Agency for Research on Cancer in 2007
• Smoking accounts for 40% of all cancer deaths, with at least 81 identified carcinogens in cigarette smoke

Additional Influences

• By-products of metabolism and errors during DNA replication contribute to carcinogenesis
• Aerobic metabolism produces mutagenic oxygen radicals
• Polymerases can introduce mutations during DNA replication and repair due to associated error rates

Carcinogenic Agents

Radiation

• Ionizing radiation (alpha and beta particles, gamma rays) damages DNA directly or indirectly through reactive oxygen species
• Ionizing radiation is the most significant damage associated with carcinogenesis, causing double-strand DNA breaks
• Ultraviolet radiation (UVB) is the most effective carcinogen, causing DNA damage through absorption and dimer formation
• UVA indirectly damages DNA via free radical-mediated damage

Chemical Carcinogens

• Many chemicals in the environment and diet play a role in human carcinogenesis
• Cytochrome P450 enzymes are involved in the metabolism of chemicals in the liver and activate carcinogens to ultimate carcinogens
• Examples of chemical carcinogens include polycyclic aromatic hydrocarbons, aromatic amines, and nitrosamines and nitrosamides
• Fibrous minerals like asbestos and erionite act as chemical/physical carcinogens and mutagens

Occupational Cancers

• Beryllium, chromium, radon, nickel, and asbestos are associated with lung cancer
• Arsenic compounds are associated with lung, skin, and hemangiosarcoma
• Benzene is associated with leukemia and Hodgkin's lymphoma
• Cadmium is associated with prostate cancer

Infectious Pathogens

• Early 20th-century studies showed that viruses can cause tumors in animals
• Oncogenic viruses encode viral proteins that block tumor suppressor genes or produce mutated forms of normal genes
• Examples of carcinogenic pathogens include:
  • Human papillomavirus (types 16 and 18) associated with cervical cancer
  • Kaposi's sarcoma-associated herpesvirus (KSHV) associated with Kaposi's sarcoma
  • Hepatitis B virus associated with liver cancer
  • Epstein-Barr virus (EBV) associated with nasopharyngeal carcinoma
  • Human T-cell lymphotropic virus type 1 (HTLV-1) associated with T-cell leukemia
  • Helicobacter pylori associated with gastric cancer
  • S. Typhi associated with hepatobiliary and gallbladder carcinoma

Age

• Frequency of cancers increases with age (55-74 years), due to accumulation of somatic mutations
• Children are affected by certain neoplasms, such as lymphoblastic leukemia, lymphoma, and retinoblastoma

Hereditary Cancers

• Hereditary cancers constitute about 5-10% of all human cancers
• Hereditary cancers tend to be bilateral and arise earlier in life
• Autosomal dominant cancer syndromes include:
  • Retinoblastoma (60% have defective tumor suppressor gene)
  • Familial adenomatous polyposis (100% develop colon cancer by age 50)
• Autosomal recessive cancer syndromes include:
  • Xeroderma pigmentosum (defective DNA repair)
• Familial cancers of uncertain inheritance include:
  • Cancers of colon, breast, ovary, and brain

Acquired Pre-Neoplastic Conditions

• Some non-neoplastic lesions increase the likelihood of developing cancer
• 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 carcinoma)