Oncogenes and Tumour Suppressor Genes

• Cancer occurs when mechanisms regulating normal cellular growth and proliferation fail, resulting in excessive cell division
• This loss of regulation occurs due to damage to the genes regulating these processes
• Only about 10% of all cancer mutations are inherited, with the majority arising as a result of environmental factors
• Cancer is not just one disease but many diseases, with approximately 200 different types of cancer identified
• Neoplasms:

  • Benign neoplasms show localized growth and grow by expansion, compression, or displacing surrounding normal tissue
  • Malignant neoplasms are capable of invasion and/or metastasis, growing by local infiltration and destroying the tissue they invade
  • Neoplasms are any new and abnormal growth where cell multiplication is uncontrolled and progressive, and they may be benign or malignant
• Models for tumour propagation:

  • Clonal evolution model: mutant tumour cells with a growth advantage are selected and expanded. All cells in the dominant population have a similar potential for initiating tumour growth
  • Cancer stem cell (CSC) model: refers to a rare subset of tumour cells that have the ability to self-renew and generate diverse tumour cells. CSCs may undergo clonal evolution, leading to the emergence of more dominant CSCs with aggressive properties
• Tumours are functionally heterogeneous and hierarchical, composed of cells that can initiate tumours (tumour initiating cells or cancer stem cells) and cells that arise from CSCs but cannot initiate tumours. The frequency of CSC in a tumour is highly variable, and CSCs have been identified in various cancers like Breast Cancer, Colon Cancer, Leukemia, and more
• Mutations in three classes of genes cause cancer:

  • Proto-oncogenes: normal activity is to promote cell proliferation, while mutant forms (oncogenes) result from gain-of-function mutations that create forms excessively active
  • Tumour suppressor (TS) genes: normal activity is to inhibit cell proliferation or promote apoptosis. In cancer, tumour suppressors are inactivated, often with both alleles affected
  • Caretaker genes: ensure accurate replication, repair, and segregation of DNA. Mutation (inactivation) of these genes leads to genomic instability
• Hallmarks of Cancer:

  • Essential changes in cell physiology
  • Described by Hanahan and Weinberg in 2011
  • Include functions of oncogenes and tumour suppressor genes
• Functions of Oncogenes and Tumour Suppressor genes:

  • Wild type function and properties of tumour-promoting mutations
  • Examples of how mutations affect cell proliferation
• Tumour suppressor genes can be inactivated by deletion, point mutation, methylation of promoter leading to transcriptional silencing, or miRNA causing post-transcriptional silencing. Examples include RB (retinoblastoma), P53, APC (Adenomatous polyposis coli), and BRCA1
• Functions of oncogenes include promoting cell cycle progression, inhibiting apoptosis, promoting DNA repair, and inhibiting cell cycle progression. Examples of well-characterized oncogenes include growth factors, cell surface receptors, intracellular signal transduction molecules, and more
• Three ways of activating oncogenes:

  1. Point mutation or deletion (e.g., H-Ras, EGFR)

  2. Amplification (e.g., MYCN)

  3. Chromosome rearrangement to create a fusion gene (e.g., BCR-ABL)
• Clinical note:

  • Gleevec (Imatinib) is a small molecule inhibitor designed to inhibit the tyrosine kinase activity of BCR-ABL
  • Imatinib has been successful in treating Chronic Myelogenous Leukemia (CML)
• Stability of genome:

  • Genomic instability is a common feature of tumour cells, including chromosomal instability (CIN) and microsatellite instability (MIN)
• The telomere and telomerase:

  • Telomeres protect chromosome ends and shorten with each cell division
  • Telomerase maintains telomere length and is active in cells requiring repeated divisions like stem cells
  • Cancer cells activate telomerase to circumvent apoptosis or senescence
• Genomic instability is a common feature of tumour cells, including chromosomal instability (CIN) and microsatellite instability (MIN)
• Telomeres protect chromosome ends and shorten with each cell division. Telomerase maintains telomere length and is active in cells requiring repeated divisions like stem cells. Cancer cells activate telomerase to circumvent apoptosis or senescence
• Read: Hanahan, Weinberg. Cell 144:646 2011 "Hallmarks of cancer: the next generation"

  Discovery of oncogenes

  Watch Clonal evolution / cancer stem cell video