Genetics of Cancer (finished)

• Types of Genetic Diseases:

  • Chromosome Disorders
  • Single Gene Disorders
  • Multifactorial or Complex
  • Sex-Linked and Mitochondrial
• Chronic Myeloid/Myelogenous Leukemia (CML): bone marrow produces excessive amounts of abnormal granulocytes at the expense of other health white blood cells

  • ABL gene from chromosome 9 and BCR gene from chromosome 22 trade places (translocation)
  • Forms the Philadelphia chromosome and the fusion of the BCR and ABL genes
  • Rare in children
  • In adults usually ages 60-65
• A single mutation is not enough to cause cancer
• Cancer or tumor formation is a somatic event involving other mutations and environmental factors
• Most inherited mutations associated with cancer affect a person's risk for developing cancer
• Cancer starts to development after accumulating about 3 mutations in a single cell
• Cancer is cause by a combination of a small number of genetic defects or hits
• Cancer is more easily found in:

  • Cells that have increased cell division and normal apoptosis
  • Cell that have normal cell division and decreased apoptosis
• Genetic Gene Inactivation: accidentally change a nucleotide sequence in DNA
• Epigene Gene Inactivation: Accident cause DNA Packaging into heterochromatin or causes methylation of C nucleotides
• Benign: excessive cell proliferation remains in the follicle of the duct 100% of the time
• Malignant Tumor: excessive cell proliferation breaks basal lamina to become exposed to other tissues
• Malignant tumors are classified by tissue/cell type that they originate
• Carcinoma: cancer from epithelium
• Sarcomas: cancer from connective tissue or muscle cell
• Leukemia: cancer from WBC and their precursors (hematopoietic cells)
• Lymphoma: cancer from lymphatic cells
• Gliomas: cancer form glial cells of CNS
• Many cancers are maintained by a population of cancer stem cells that have the ability to self-renew, initiate tumors, and give rise to more differentiated cells
• Transit-amplifying cells (TACs): undifferentiated cells that act as bridge between stem cells and differentiated cells
• Cancer stem cells generally divide more slowly
• Cancer stem cells may survive radiation or chemtherapy
• Tumors secrete angiogenic signals that promote formation of new blood vessels needed to supply nutrience needed for a growing tumor

  • New blood vessels can be affected by metastasis and can colonize distant sites
• Cancer cells:

  • more self-sufficient than normal cells
  • relatively insensitive to antiproliferative extracellular signals
  • less likely to undergo apoptosis
  • are defective in control mechanisms that usually halt cell division
  • induces help from normal stormal cells in their microenvironment
  • induces angiogenesis
  • can survive and proliferate in foreign sites
  • genetically unstable
  • produce telomerase or acquire some way of stabilizing telomeres
• Cancer Gene Classifications:

  • Normally inhibit cellular proliferation
  • Activate proliferation
  • Participates in DNA repair
• Proto-oncogenes: control cell growth and division

  • When proto-oncogenes mutate to oncogenes, it activates when not suggested and causes uncontrolled cell division
• Anti-oncogenes (tumor suppressor genes): normal genes that slow down dell division, repair DNA mistakes, enforces apoptosis
• Cancers can grow with the activation of proto-oncogenes and the inactivations of turmor suppressor genes
• Retinoblastoma (Rb) protein: "universal" cell cycle regulator that's a break on cell cycle progression
• Alfred Knudson 2-Hit Hypothesis: 1971; A person would need to acquire two mutant copies of Rb gene

  • Hereditary retinoblstoma: first mutation or hit occurs in germline, second hit occurs in somatic cell
  • Nonhereditary rb: both hits occur in somatic cell
• 90% of individuals who inherit mutant allele experience a second hit and develop a tumor
• Tumor suppressor genes p16 and Rb work together to regulate cell cycle

  • P16: Cdk inhibitor that slows cell cycle by inactivated kinases that phosphorylate Tb
  • Rb: transcriptional corepressor that form complexes with E2F transcription factors to inhibit cell roliferation
• The inactivation of p16 can activate cyclinD-Cdk4 complex, leading to inactivation of Rb and activations of E2F
• p53 protein: tumor suppressor protein that regulates cell division and DNA repair
• p53 prevents cells from dividing too fast or in uncontrolled way through repairing damage or undergoing apoptosis
• p53 activates genes that fix damaged DNA
• p53 prevents development of tumors by stopping cells with damaged DNA from dividing or signals the cell to undergo apoptosis
• p53 is deemed the guardian of the genome
• Mutations in p53 gene are found in most tumor types
• Stimuli that can trigger a stable and active p53:

  • Hyperproliferative signals
  • DNA damage
  • Telomere shortening
  • Hypoxia