Neoplasia II

• Cancer epidemiology looks into the environmental, racial, and cultural influences to the occurrence of specific neoplasms
• Cancer Incidence (2012)

  WHO estimated 14.1M incidence of cancer worldwide leading to 8.2M deaths
• Due to increasing population

  WHO predicted that by the year 2035, the number of cancer cases and deaths worldwide will increase to 24M and 14.6M, respectively
• Over several decades, there were noted decrease in the incidence of some specific cancers
• Decrease in Lung Cancer

  Due to decrease use of tobacco products
• Decrease in death rates for Colorectal, Breast, and Prostate Cancers


  Due to improved detection and treatment
• Dominant risk factors for many common cancers

  • Carcinogens (naturally occurring or man-made)
  • Diet (Obesity)
  • Smoking
  • Alcohol Consumption
  • Reproductive History
  • Infectious Agents
• A high fraction of cancers are potentially preventable
• Carcinogens


  Any substances that may cause cancer
• In general the frequency of cancer increases with age


  Due to accumulation of somatic mutations and decline in immune competence
• 10% of deaths due to cancer among children 15y/o and below
• Cancers common in children

  • Leukemias
  • Lumphomas
  • Soft tissue and Bone sarcoma
  • CNS neoplasms
• Acquired Predisposing Conditions


  Conditions that increases the risk of cancer development
• Examples of Acquired Predisposing Conditions


  • Chronic inflammation
  • Immunodeficiencies
  • Precursor lesions (Squamous metaplasia and dysplasia of bronchial mucosa, Endometrial hyperplasia and dysplasia, Leukoplakia, Villous adenoma of the colon)
• Reversal or removal of precursor lesions may lower the cancer risk
• Cancer Genes


  Genes that are recurrently affected by genetic aberrations in cancers presumably because they contribute directly to the malignant behavior of cancer cells
• Causative mutations in cancer genes

  May be acquired by the action of environmental agents (carcinogens) or inherited in the germ line
• Oncogenes


  Genes that induce a transformed phenotype when expressed in cells, promote proliferation
• Tumor suppressor genes


  Genes that normally prevent uncontrolled growth, when mutated or lost, allows the transformed phenotype to develop
• Tumor suppressor genes


  • Cell cycle regulator genes, checkpoint genes, apoptosis related genes (act as important breaks on cellular proliferation)
  • DNA repair proteins (responsible for sensing genomic damage, initiate and choreograph a "damage control response")
• Genes that regulate apoptosis

  Primarily act by enhancing survival rather than stimulating proliferation, protect against apoptosis
• Genes that regulate interactions between tumor cells and host cell

  May enhance or inhibit recognition of tumor cells by the host immune system
• Driver Mutations


  Mutations that alter the function of cancer genes and directly contribute to the development or progression of a given cancer
• Passenger Mutations


  Acquired mutations that occur at random and do not affect cellular behavior
• Specific Mutations


  • Point mutations
  • Gene Rearrangements
  • Deletions
  • Gene Amplifications
  • Aneuploidy
  • MicroRNAs
• Point mutations


  Can either activate or inactivate the protein products of the affected genes
• Gene Rearrangements


  May be produced by chromosomal translocations or inversions, highly associated with neoplasms of the hematopoietic cells and other mesenchymal cells
• Deletions


  Deletion of specific regions of chromosome resulting in loss of particular tumor suppressor genes
• Gene Amplifications


  Proto-oncogenes may be converted to oncogenes by gene amplification with consequent overexpression and hyperactivity
• Aneuploidy


  Defined as a number of chromosomes that is not a multiple of the haploid state, frequently results from errors of the mitotic checkpoints
• MicroRNAs


  Non-coding, single-stranded RNAs that function as negative regulators of genes, inhibit gene expression posttranscriptionally by repressing translation, contribute to carcinogenesis by specifically targeting oncogenes and tumor suppressor genes
• Carcinogenesis is a multi-step process resulting from the accumulation of multiple genetic alterations that collectively give rise to cancer
• Hallmarks of Cancer


  • Self-sufficiency in growth signals
  • Insensitivity to growth-inhibitory signals
  • Altered cellular metabolism
  • Evasion of apoptosis
  • Limitless replicative potential (immortality)
  • Sustained angiogenesis
  • Invasion and metastasis
  • Evasion of immune surveillance
• Carcinogenic Agents


  Agents that inflict genetic damage
• Classes of Carcinogenic Agents

  • Chemical Carcinogens
  • Radiant Carcinogens
  • Microbial Products
• Direct-Acting Chemical Carcinogens


  Require no metabolic conversion to become carcinogens, typically weak carcinogens, accumulation may induce carcinogenesis
• Indirect-Acting Chemical Carcinogens


  Require metabolic conversion to induce carcinogenesis
• Direct-Acting Chemical Carcinogens


  • Chemotherapy drugs (cyclophosphamide, chlorambucil, nitrosoureas)
• Indirect-Acting Chemical Carcinogens


  • Benzopyrene formed during combustion of tobacco (Lung cancer)
  • Benzopyrene during burning of coal (Scrotal cancer among chimney sweepers)
  • Aromatic amines and Azo dyes used in aniline dye and rubber industries (Bladder cancer)
• Radiation Carcinogenesis


  Radiation is an established carcinogen irregardless of its source (UV rays from sunlight, radiographs, nuclear fission, radionucleotides)