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Cancer Genetics
 

Cancer Genetics

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  • Cancer is a common disease in the developed world. 1 in 3 of us will develop cancer if we lived long enough. Although treatments, including surgery, chemotherapy and radiotherapy, are continually improving, half of the individuals with cancer will still die from the disease.
  • All cancer is genetic because genetic alterations (mutation) are at the very centre of tumourigenisis, so that at a cellular level cancer can be designated a genetic disorder. However Only a small proportion of the total number of cancers are thought to be inherited (~5%)
  • Genetic mutations can be aqcuired or inheritied Acquired mutations are mutations that develop often during the process of DNA replication and cell division. They are also referred to as somatic mutations and they are only present in the descendents of they cell that they originate in. Inherited mutations, also called germline mutations, are present from the very first cell, and are present in every cell in the body.
  • Most cancers are sporadic cancers, they arise from the accumulation of acquired mutations in our genome. The principle environmental agents are those such as cigarette smoking, chemicals and radiation that cause our genome to acquire mutations. Other agents such as viruses are also implicated. So although all cancer is genetic, not all cancer is inherited. However it is the same genes that are involved in the genesis of both environmental and inherited cancers. Also our susceptibility to environmental agents such as smoking, may be genetically determined.
  • In 1997 Kinzler and Vogelstein coined the terms Gatekeeper and caretaker to distinguish between the cancer susceptibility genes that act directly to control cellular proliferation and differentiation (gatekeepers) and those genes that maintain the integrity of the genome (caretakers) Gatekeepers May be divided into 2 classes – Oncogenes that produce a positive effect on cell growth and proliferation and tumour suppressor genes that have a negative effect. Caretaker genes are those genes that are responsible for the repair of replication error that occur during the cell cycle.
  • Oncogenes have a positive effect on the regulation of the cell cycle, cell division and differentiation. So if oncogenes are mutated this can lead to permanently activated cells. One way to think about oncogenes is to liken them to an accelerator in a car. If the accelerator is stuck on the car will go faster and faster and the driver loses control of the car. If an oncogene is permanently switched on the control of the cell proliferation is lost and mutated cells are produced at a faster and faster rate. Although mutations in the oncogenes are important in production of a malignant tumour – inherited mutations in these genes that cause genetic predisposition to cancer are rare. Mutations in these genes are usually acquired mutations. One exception is RET gene activation in MEN2.
  • Tumour suppressor genes have a negative effect on cell growth and proliferation. Their function is to induce apoptosis and they act in a recessive manner by the loss of their function. Again if we use the car sinario and liken the tumour suppressor to the brake on a car. A normally functioning brake will be abe to slow the car down and gives the driver contorl over the speed of the car. If however the brake does not work then the driver loses control of the car’s speed. If tumour suppressor genes do not work properly then cells that should die off do not and they are allowed to continue to replicate increasing the chances of further mutations being acquired.
  • The 2 strands are therefore complimentary to each other - One strand can be predicted from the other. Here is a sequence of code. Can you tell what the complementary sequence is? Using this process of replication the genetic code is maintained during cell division. The process is called semi-conservative replication.
  • TS is an AD condition, This is a typical AD pedigree. What aspects of the pedigree show that the mode of inheritance is AD

Cancer Genetics Cancer Genetics Presentation Transcript

  • Cancer Genetics Diane Stirling Clinical Nurse Specialist
  • Cancer
    • Affects 1 in 3 people in developed world
    • Approximately half will die
    • The other half may experience treatments such as-
      • Surgery
      • Chemotherapy
      • Radiotherapy
    • Cancer occurs because of mistakes (mutations) in the DNA that controls cell growth and proliferation
    • However
    • Only a small proportion of the total number of cancers are thought to be INHERITED (~5%)
    All Cancer is GENETIC
  • Mutations
    • Acquired mutations
      • Also called somatic mutations
      • Present only in the descendants of the cell that they originally occur in
    • Inherited mutations
      • Also called germline mutations
      • Present in every cell in the body
  • Acquired Mutations
    • Environmental agents, carcinogens, are continually causing mistakes to arise in our DNA.
    • Other agents - viruses
    • These are usually repaired (e.g. ‘DNA repair mechanisms’)
  • Cancer Development
    • A cancer usually arises from one single cell which has managed to escape normal cell growth controls becoming uncontrolled and keeps dividing
    • A growth develops which can invade neighbouring tissues and spread by lymph or blood.
  • A Multi-Step Process
    • Cells are continually making DNA (replicating) then dividing into new cells (mitosis), differentiating into other cell types or dying (apoptosis)
    • This is the ‘cell cycle’.
    Cell Cycle
  • Cell Cycle Control
    • GATEKEEPERS
      • Oncogenes (proto-oncogenes)
        • positive effect on growth and proliferation
      • Tumour Suppressors
        • negative effect i.e. suppress growth
    • CARETAKERS
      • DNA Repair Mechanisms
  • Oncogenes (proto-oncogenes)
    • Proto-oncogenes have positive effect on regulation of the cell cycle, cell division and differentiation
    • When proto-oncogenes are mutated they are called oncogenes
    • Oncogenes can lead to permanently activated cells
    • Accelerator
  • Tumour Suppressors
    • Negative effect on regulation of the cell cycle, cell division and differentiation
    • Induce apoptosis
    • Brakes
  • DNA Repair Genes
    • Caretakers
    • Repair DNA mutations caused by replication errors, carcinogens etc
    • Base-pairing rules
    • A pairs with T
    • G pairs with C
    • vice versa
    • Pairing is by H-bonds
    • G-C pairing stronger than A-T
  • A T C T A G T A G A T C Semi – conservative replication A T C T A G Original double strand DNA separates and replicates 2 new double strands – each containing one parent and one daughter strand T A G A T C A T C T A G
  • A G C G A T C T G G DNA Base Pairing Mismatch Repair T C G C T A G A C C A C
  • Cancer - A multi step process Tumour Suppressor genes DNA Repair Environmental Mutagens Activated Oncogenes Loss of Tumour Supressor genes Loss of DNA Repair Apoptosis
  • so...
    • Cancers (whether sporadic or hereditary) arise by the activation, in one cell, of oncogenes and loss of tumour suppressor function. These occur by mutations, deletions, replication errors etc
    • Loss of normal DNA repair mechanisms can aid this process
  • Inherited cancers - oncogenes
    • Not usually inherited (one exception is RET gene in MEN2)
    • Act dominantly to induce or maintain cell transformation – only one copy of the gene pair needs to be mutated
    • Each malignant tumour type has it’s own characteristic spectrum of oncogene mutations (sporadic)
  • Inherited Cancers – tumour suppressor genes
    • Tumour suppressor mutations are responsible for a number of cancer predisposition syndromes
        • Li- Fraumeni syndrome
        • Von Hippel-Lindau
        • Tuberous Sclerosis
        • Retinoblastoma
        • Familial Breast and Breast /Ovarian Cancer
    • Act in a recessive manner, (ie loss of protein function, LOH)
  • Knudson’s Two-hit Hypothesis (Tumour Suppressors)
    • Developed in 1971 based on retinoblastoma gene (RB1)
    • Retinoblastoma is a rare childhood cancer
    • If inherited- onset is younger and often multiple/ bilateral retinoblastoma
  • Knudson’s “Two Hit” Hypothesis Cancer Inherited Change FIRST HIT Acquired Change SECOND HIT Acquired Change SECOND HIT Acquired Change FIRST HIT No Change CANCER Inherited Sporadic
  • Familial Adenomatous Polyposis (FAP)
    • Example of the two hit theory
    • An inherited germline mutation in one copy of the apc gene pair leads to dozens of benign polyps
    • A somatic mutation then needs to be acquired on second copy of the gene (plus other mutations) before a polyp becomes cancerous
  • FAP – as an example of a multi-step process Normal epithelium Hyper proliferative epithelium Early Adenoma Intermediate adenoma Late adenoma Carcinoma Metastasis Loss of apc Activation of K-ras 18q deletion Loss of p53 Other changes...
  • Inherited Cancers – mismatch repair genes
    • An inherited mutation in a MMR repair gene results in an increased mutation rate in the genome
    • The increased mutation rate leads to accelerated tumour progression
    • Known to be involved in hereditary Bowel Cancer- MLH1, MSH2, MSH6 etc
  • Cancer - A multi step process Tumour Suppressor genes DNA Repair Environmental Mutagens Activated Oncogenes Loss of Tumour Supressor genes Loss of DNA Repair Apoptosis
  • So again...
    • Cancers (whether sporadic or hereditary) arise by the activation, in one cell, of oncogenes and loss of tumour suppressor function.
    • Loss of normal DNA repair mechanisms can aid this process
  • Therefore inherited predisposition to cancer (hereditary cancer)
    • arises from an accumulation of inherited and somatic mutations in oncogenes, tumour suppressor genes and DNA repair genes
    • multistep processes
    • However, one step is already present in all cells in hereditary cancer
    • Penetrance - proportion of individuals with a gene type who show the effects (usually a percentage)
    • Variation - the differences in expression of a gene type (physical affects)
  • Sporadic vs Hereditary Cancer
    • Approximately 5% of cancer is due to an inherited predisposition
    • When is a cancer hereditary?
  • Family History
    • Dominant pattern of inheritance (with non-penetrance)
    • Increased number of individuals affected on one side of the family
    • Younger age of onset
    • Multiple primaries e.g. bilateral breast
    • Patterns (breast/ ovarian, bowel/ endometrial) or rare cancers
    • involvement of more than one generation
    • male to male transmission
    • males and females affected equally
    Autosomal Dominant Inheritance Affected Unaffected
  • 45 27 36 42 Breast cancer Hereditary Breast Cancer 48
  • 26 35 29 47 31 Breast cancer Ovarian cancer 48 58 Hereditary Breast/Ovarian Cancer
  • 47 45 29 35 37 52 41 Endometrial Cancer Stomach Cancer Colorectal Cancer Hereditary Bowel Cancer - HNPCC
  • Genes and Environment Disease Inherited Genetic Factors Environmental Factors
  • Sporadic Cancer Disease Environmental Factors Inherited Genetic Factors
  • Hereditary Cancer Disease Inherited Genetic Factors Environmental Factors
  • Summary
    • Both hereditary and sporadic cancer is a multistep process involving oncogenes, tumour suppressor genes and MMR genes
    • Inherited mutations are mainly tumour suppressors or MMR genes
    • Dominant inheritance
      • but TS genes act recessively at cellular level
      • Knudsons 2 hit hypothesis
  • How to Reduce Environmental Risk?
  • Healthy Eating!!! Fresh fruit + vegetables
  • Fibre / Resistant starch Aspirin(NSAIDS) Calcium Green bananas
  • + Anti- carcinogenes Garlic Tea (especially green tea) Oily fish Red wine Folates Olive Oil
  • Fat Sugar UV Burnt food Salt/ Nitrates/ H.pylori Mould
  • Keep fit
    • Hormones