Chapter 5 Notes

• Tumour suppressor genes (TSGs)


  • They are antigrowth genes
  • They are lost in cancer (loss-of-function mutations)
  • Loss of TSGs promote cancer growth
• Tumour suppressor genes


  Genes that are lost in cancer due to loss-of-function mutations
• Proto-oncogene


  • Gain-of function mutation
  • Loss-of function mutation
• ONCOGENES


  Dominant genes
• TSGs


  Recessive genes
• TWO-HIT OR KNUDSON HYPOTHESIS

  1. Mutations in two TSGs alleles lead to abnormal growth

  2. In order for a cell to become cancerous, both TSG alleles must be mutated
• Retinoblastoma is a pediatric tumor that arises from a stem cell precursor of the cone cells
• Children with bilateral (familial) retinoblastoma have a high risk of developing non-retinal tumors
• The rate of appearance of familial tumors is consistent with a single random event, while sporadic tumors behaved as if two random events are required for their formation
• Dynamics of retinoblastoma formation

  Only a single somatic mutation is needed to eliminate Rb function in familial retinoblastoma, while two somatic mutations are required in sporadic retinoblastoma
• The probability of inactivating both copies of a TSG is very unlikely
• Second hit mutation in TSG is unlikely due to a low mutation rate
• Elimination of wild-type Rb gene copies

  Recombination between one chromatic arm carrying the wild type allele and a chromatid from the paired chromosome carrying the mutant allele occurs during active cell proliferation in G2 phase of the cell cycle, leading to loss of heterozygosity (LOH)
• Gene conversion can lead to loss of heterozygosity
• Replication


  Switches templates by leaving the original template strand and forms a complementary strand belonging to the chromosome (hybrid)
• Template strand


  Original strand used in replication to form a complementary strand
• Template strand of homologous chromosome

  Jumping of Polymerase between chromosomes
• Mutation


  A mutated TSG may be transmitted from one chromosome to its homolog, replacing the wild-type allele located there
• Chromosomal nondisjunction


  Can lead to LOH (Loss of Heterozygosity)
• Loss of an entire chromosome due to inappropriate segregation at mitosis results in triploidy where both chromatids are retained
• Loss of Retinoblastoma (Rb) gene on chromosome 13q14
• Through replication error, certain bands can be lost
• Mutations of the Rb gene


  • In Retinoblastoma and Osteocarcinoma
• Internal regions of the gene were lost due to mutational inactivation
• Detecting LOH in tumors

  Restriction fragment length polymorphisms
• Single nucleotide polymorphism (SNP) arrays use DNA hybridization with array probes to detect genetic alterations
• Fluorescence intensity allows knowing how much of the hybridized probe was sticking to the sequence
• Promoter methylation can inactivate TSGs
• Epigenetics involves the regulation of gene expression through DNA methylation and chromatin structure organization
• Chromatin


  Consists of DNA wrapped around histones (proteins)
• Nucleosomes


  Contain 2 copies each of H2A, H2B, H3, and H4 histone proteins
• DNA methylation of promoters leads to transcriptional repression
• Demethylation and methylation are driving forces of cancer
• Hypermethylation of TSGs promoters is observed in many different cancers
• Demethylation of TSGs promoters leads to the inactivation of TSGs
• Restriction digest is needed for the MAPK pathway involved in repressor function
• Neurofibromatosis type 1 is a familial cancer syndrome caused by the loss of the Nf1 gene
• APC gene is associated with colon cancer
• Neurofibrosarcomas are malignant tumors of neurofibromas
• Neurofibromas can progress to malignant neurofibrosarcomas