Oncogene co-operation and biomarkers

• How are RTKs signalling hubs?

  • Can activate many kinases and transcription factors
  • Each receptor has many different phosphorylation sites, which bind to signalling molecules
  • Results in activation of multiple signalling pathways

  
• Describe the action of Myc

  • Basic helix loop helix transcription factor
  • Involved in cell proliferation, differentiation, apoptosis and metabolism
  • Forms a heterodimer with Max and this complex binds to specific DNA sequences called E boxes
  • Myc has a half life of around 20 minutes, and it rapidly degraded by the proteasome, which acts as a the main mechanism for regulation
• What is the FISH test?

  • Fluorescently labelled DNA probe that fluoresces when it binds to the gene of interest
  • More copies of the gene = more fluorescence, which can be used to detect gene amplification in cancer
• How is Myc mutated in cancer?

  • Myc is constitutively active and aberrantly expressed in over 70% of human cancers
  • Increased stabilisation of Myc increases its half life and increases activation.
  • Dysregulation of Myc results in higher concentrations of Myc, allowing to bind to both high and low affinity genes and creates an abnormal cell cycle
• Describe Ras and Myc cooperation

  • Independent Ras and Myc mutations result in immune surveillance and cell death
  • Ras and Myc mutations synergise to evade the immune system and produce greater tumour growth
• What is gene expression profiling?

  • Analysis of the activity of thousands of genes simultaneously to understand how they are being expressed in a particular cell or tissue.
  • In the context of cancer, gene expression profiling has been used to classify tumours.
  • The information derived from gene expression profiling often impacts prognosis and treatment pathways for patients
• Describe the molecular profiling of breast cancer

  • HR+ tumour cells have receptors for oestrogen and progesterone, which promotes their growth
  • HER2+ tumour cells can make high levels of human epidermal growth factor receptor 2
  • Most common, 68%, is HR+, HER2-
• Describe HER2 mutations in breast cancer

  • HER2 is an RTK, which plays a role in cell growth, differentiation, and survival
  • HER2 overexpression can lead to cell growth and division
  • HER2+ cancers typically are treated with targeted therapies such as trastuzumab, which is a monoclonal antibody that inhibits HER2
• What is the point of molecular profiling?

  • Allows patients to receive more specific diagnosis and prognosis
  • Maximises patient survival