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POM > Genes and Cancer > Flashcards

Genes and Cancer Flashcards

1
Q

What environmental factors that causes damage to DNA

A

Chemical substances (carcinogens of smoking)
Radiation (therapeutic, nuclear, atomic bomb survivors)
Viruses
-all associated with increased incidence of cancer

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2
Q

Cancer genetics

A
  • Cancers are induced by mutations in cancer causing genes (therefore consider cancer as a genetic disorder)
  • Acquired or somatic mutations in majority (cannot be inherited)
  • In some cases the mutations may be inherited (familial cancers) - mendelian (familial breast/colorectal cancer) + susceptibility genes
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3
Q

Genes which cause cancer

A

Abnormal growth of tissue giving those cells a proliferative advantage
-Oncogenes
-Tumour Suppressor Genes
-Genes involved in regulation of apoptosis (cell death)
–>cells may not be reapidly proliferating, but impairment of normal death pathways
-Epigenetic changes
-Abnormalities of DNA repair genes
-Non coding RNA – e.g. microRNA (effect regulation of gene expression)
(mutations/changes in other pathways that contribute to development or progression of cancer)
Normal tissue: Homesostasis
Roads to Neoplasia: Proliferation –Neoplasia–> Death

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4
Q

Ongogenes

A

Dominant acting genes – transform cells
(requires a mutation of a single allelle in the oncogene only to transform cells to give growth/proliferative advantage)
Initially recognized in viral induced tumours
Normal state = proto–oncogene
-switched on when cells divide and then switched off (carefully regulated)
Activated by mutation to oncogene (able to transform a cell)
Proto-ongogene –Mutation–> Ongogene

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5
Q

Function of Oncogene

A

Most involved in signal transduction

  • Growth factors
  • Growth factor receptor (more common) (e.g. point mutation, causing it to be constitutively active in absence on ligand binding)
  • Intracellular signal transmission
  • Nuclear transcription factors
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6
Q

Hyperactive growth control pathway

A

Growth factor –> Receptor –> Scanning Enzymes –> Cell Nucleus –> Transcription factors –> DNA –> Excessive Cell Proliferation

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7
Q

Transform normal cells to neoplastic cells

A

Ongogenes transform Normal cells –> Neoplastic cell
-may grow independently of growth factors
Increased cell proliferation
Block normal cell differentiation/maturation
(malignant cells have increased proliferation but also immature (lack normal differentiation of epithelial cells)
Initiation event
Tumour progression

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8
Q

What are the 2 main features of Malignant cells

A

Increased Proliferation

Immature (lack normal differentiation of epithelial cells)

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9
Q

Diagram of activation of Oncogenes

A

Proto-oncogene —> (environmental) Cancer causing (UV light, chemicals etc) –> Oncogene –> Cancerous Phenotype

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10
Q

Activation of Oncogenes (molecular level changes)

A
  1. Gene amplification
  2. Over expression of gene (change promotor to make more mRNA and hence more Protein)
  3. Point mutations
    (change critical base pairing, change a/acid, resulting in sig. change in function of proto-oncogene)
  4. Chromosome Translocations
    (swapping of chromosome material, and if involving proto-oncogene, can lead to activation to an oncogene)
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11
Q

Amplification of Onocogenes

A
  1. Neuroblastoma (paediatric tumour, will respond to chemo)
  2. N-myc amplification (nuclear transcriptional regulator of a number of critical genes)
  3. Unfavourable prognosis (amplification fo N-myc is a prognositc factor that carriers worse prognosis and would alter treatment if present)
    - Increased gene copy number
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12
Q

FISH of Amplification of Oncogenes

A

DNA probe that binds to the neuroblastoma proto-oncogene
labelled with red fluorescent probe
let hybridise onto cells
looked at under fluorescent microscope
Amplification of N-myc proto-oncogene = multiple (more than 2) dots
-gives pathogenesis of tumour
-gives clinical info that alters therapy

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13
Q

HER-2 amplification in breast cancer

A

Red signal = HER-2 gene (on chromosome 17)
-look for its amplification on FISH study
Green signal = ch 17 centromere
Amplification = more than 2 genes

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14
Q

Clinical significance of HER-2 amplification

A

HER-2 is a proto-oncogene - it encodes for an epidermal growth factor receptor in mammary cells (ETFr)
The HER-2 protein is over-expressed in 30% of breast cancer patients.
In 90% of cases, this is due to amplification of the HER-2 gene (pathogenesis. not initiating event but important in progression)
HER-2 is a target for the antibody herceptin (targeted antibody therapy)
-important part of therapy with cytotoxic drugs

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15
Q

Where is the HER-2 gene located?

A

Chromosome 17

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16
Q

Clinical significance of HER-2 amplification Diagram

A

HER-2 Gene amplification in Breast Cancer (chromosome 17 (normal))

  • -> HER-2 gene amplification, 20-30% of breast cancer patients
  • -> Increased expression of HER-2 mRNA
  • -> Increased expression of HER-2 protein
  • -> Signals cels to proliferate, tumours more aggressive –> Breast cancer cell
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17
Q

HER-2 Targeted Therapy

A

HER2 oncogene amplification in the tumour cell changes RNA and results in HER2 protein over expression
Herceptin targets HER2 Epidermal growth factor Receptor-2 protein
-binds and blocks off so EGF cannot bind

18
Q

HER2 and EGF meaning

A 
HER2= Human Epidermal growth factor Receptor-2
EGF= Epidermal Growth Factor
19
Q

Activation of oncogenes: Over expression of gene

A

Results in increased mRNA and hence increased protein expression

  • normal copy number of genes
  • but mutations/changes in promotor/regulatory regions will result in increased copy number
20
Q

Activation of oncogenes: Point mutations

A

Quite common
Single base change, but if is a change of a critical a/acid, can lead to constitutive activation of a signalling pathway
Mutations within EGF receptor allows it to be active without binding its ligand, activating down stream signalling pathways –> Gene transcription –> Cell cycle activation
–> Increased Survival, proliferation and invasion(into lymphatics and BV)

21
Q

How do chromosome translocations activate proto-oncogenes ?

A 
(if chromosome translocation brings 2 genes together in 5 prime 3 prime configuration) 1. Form fusion gene (-->fusion mRNA) which encodes for novel protein with increased activity
eg t(9;22) in chronic myeloid leukaemia
2. More common. Increased expression of oncogene e.g. by translocation moving adjacent to actively transcribed gene or promoter region (constitutively active) e.g. the immunoglobulin gene in B cell cancers (would result in up-regulation/increased expression of the proto-oncogene)
22
Q

Myc translocations in Burkitts Lymphoma

A

Lymphoma= cancer of lymphoid tissue
Burkitts Lymphoma is one of the most aggressive cancers
-cells developing every 24-48hrs
presented with abdominal pain
-mass which is dark centrally (necrotic/outgrown blood supply)
-biopsy chows Burkitts Lymphoma
–Monomorphic population of immature cells
-dark, alot of mitotic figures, actively dividing
-90% of Burkitts Lymphoma will have Chromosome translocation/abnormaltion (most common is c 8 is attached to 14) (some 8 and 22. others 2 and 8)

23
Q

Significance of Myc translocation in Burkitts Lymphoma

A

Long arm of Chromosome 8 contains protooncogene myc
-seen in neuroblastoma
-myc codes for a transcriptional factor
Chromosome 14 contains IgHeavy chain gene
Chromosome 2 and 22 contain IgLight chain genes
Translocations: takes myc protooncogene and places into 5’ to 3’ configuration with Ig gene
-since in lymphoid cell, Ig gene promotor regions are always activation –> upregulation of expression of myc onocogene –> increased transcription of other downstream genes

24
Q

Tumour Suppressor Genes

A

Recessive acting or “anti-oncogenes”
-regulate cell growth (“suppressors”)
Requires loss of activity – of both alleles (mutation of both allelles for TSG to contribute to malignant phenotype)
Often mechanism in familial cancers – one inherited mutation in TS gene with second acquired mutation causing loss of activity of the other allele

25
Q

Tumour Suppressor genes Accelerators vs Brakes

A

Accelerators (oncogenes): Substances that encourage growth –> Substances that trigger cell division
Brakes (TSG): Substances that prevent growth –> Substances that stop cell division

26
Q

Tumour suppressor Gene diagram

A

Wild type TSG –New Mutation –>
First “hit” (e.g. a mutation in one copy of the TSG) –Deletion–>
Second “hit” (e.g. a deletion in the other copy of the TSG) –>
Progression to tumour formation
Nots: Frequently implicated in familial cancers (First “hit” (the germline mutation) is an Inherited Germline mutation in the TEG
-compatible with life, as doesnt result in malignant phenotype, until mutation effecting the other allele, –> progression to tumour

27
Q

Retinoblastoma

A

“Two hit hypothesis”
Paediatric tumour
Rare
2x types: Hereditary or Non-Hereditary
1. Hereditary: Family history, Autosomal Dominant. Bilateral (both eyes, or two tumours in one eye). Early onset. Germline-mutation of Retinoblastoma gene.2nd hit resulted in tumours (all cels predisposed so not unexpected to multifocal tumours within one cell)
2. Non Hereditary: Sporadic form. Unilateral. Late Onset. later childhood). Retinoblastoma gene was normal/wild type. required 2x somatic/acquired hits within the same cell, before tumour developed. (single tumour and late onset)
Retinoblastoma gene on Chromosome 13 is a cell cycle regulator, inherited form had a germline mutation. (every cell had this mutation)

28
Q

Apoptosis - Programmed Cell death

A

a) Normal Tissue
in –> Homeostasis –> Out
b) The roads to Neoplasia
-Increased proliferation –> Neoplasia –> Death
-Proliferation –> Neoplasia –> Death
(arent giving cell proliferative advantage, the cell just dont die by normal programmed cell death pathway)

29
Q

Genes which affect apoptosis

A
  1. Upregulation of genes which encode for proteins that block apoptosis
    - make “blocking” cell death pathway proteins. Single mutation
  2. Loss of activity of genes which encode for proteins that mediate apoptosis eg fas, p53
    - recessive action - have to lose both alleles
30
Q

Pathways of Apoptosis

A
  1. Stress pathway Cell damage, activation of oncogenes, growth factor deprivation
  2. Death receptor Pathway: Ligands (Fast, TRAIL, TNF)
    - —-> Cell Death
31
Q

Summary: Genes in cancer

A
  1. Oncogenes
    - Dominant acting
    - Promote cell growth
  2. Tumour suppressor genes
    - Loss of activity
    - Inhibit cell proliferation
  3. Genes involved in apoptosis
32
Q

Multistep process

A

Cancer is a multistep process…
Most cancers involve multiple genetic events or hits before the full cancer phenotype develops
Mutation inactivates tumour suppressor gene –> Cells Proliferate –> Mutation inactivates DNA repair gene –> Mutation of proto-oncogene creates oncogene –> Mutation inactivates several more tumour supressor genes –> Cancer

33
Q

Epigenetic changes in cancer

A

Not mutation of cancer causing genes. Rather the way DNA is packaged.
Effects Methylation and status. + the role of Non-coding RNA related to packaging

34
Q

What is the clinical relevance ? (Personalized medicine based on cancer genomics)

A

Personalized medicine based on cancer genomics
• Molecular diagnosis and classification of tumours (molecular markers) (HER2 +ve cancer) (B2 melanoma)
• Prognostic markers (Nmch amplification)
• Targets for therapy
• Markers to monitor response to therapy
• Biomarkers eg cell free DNA

35
Q

What is the clinical relevance ? (Application to familial cancer)

A

Application to familial cancer
Understanding molecular genetics allows introduction of predictive / at risk genetic testing
Allows screening strategies, potential to reduce other risk factors, prophylactic surgery

36
Q

What is the clinical relevance Cycle

A

Genome technologies –>
“Individualised” profile of cancer alterations –>
Target therapy trials (Cancer genome alterations) –>
Diagnosis and prognosis for individual patients –>

37
Q

Cancer Therapies that target oncogenic proteins

A 
Anticancer Drug --> Disease
Monocolonal antibodies:
Trastuzumab (Herceptin) --> Breast Cancer
Small Molecules:
Imatinib --> Leukemia markers
38
Q

Chronic Myeloid Leukaemia (CML)

A

Clinical features:
• High white blood cell count
• Splenomegaly
• Chromosomal abnormality
-all have The Philadelphia Chromosome: t(9;22) Translocation
-Protoncogene 9’s c abl (weak tyrosine kinase) into a 5’ to 3’ configuration with 22’s bcr gene –> bcr-abl
–> Fusion protein with very potent tyrosine kinase activity

39
Q

The Philadelphia Chromosome:

A

Tyrosine kinases are present in most cancers and involved in signalling pathways
Acquired chromosomal translocation seen in chronic myeloid leukaemia
Clinical Implications:
-Diagnostic criteria for CML (required)
-Leukaemogeneic (will develop leuakemia)
-Target for therapy
-Biomarker to monitor response to therapy

40
Q

Bcr-Abl as a Therapeutic Target

A

Bcr-abl uses ATP to phosphorylate tyrosine residues
switches on down stream signalling pathways making the cells proliferate
Imatinib binds into ATP binding pocket, stopping proliferation, cells die via apoptosis

41
Q

Imatinib (glivec) 5 year data

A

Clinical remission 98%
Cytogenetic remission 87%
Overall survival at 5 yrs 89% (95%)
Pre – Imatinib median survival CML 5 years
Patients in complete cytogenetic remission > 2 years
-chemo therapy half dead in 4 years

42
Q

Chronic Myeloid Leukaemia

A

Model for genetics and therapy of cancer

  • Acquired cytogenetic / molecular abnormality
  • Results in proto-oncogene activation with formation of a potent tyrosine kinase
  • Key pathogenic event present in leukaemic but not normal cells
  • First example of targeted cancer therapy

POM (33 decks)

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