Genes and Cancer Flashcards by sita clark

What environmental factors that causes damage to DNA

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

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Cancer genetics

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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Genes which cause cancer

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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Ongogenes

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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Function of Oncogene

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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Hyperactive growth control pathway

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

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Transform normal cells to neoplastic cells

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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What are the 2 main features of Malignant cells

Increased Proliferation

Immature (lack normal differentiation of epithelial cells)

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Diagram of activation of Oncogenes

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

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Activation of Oncogenes (molecular level changes)

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

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Amplification of Onocogenes

Neuroblastoma (paediatric tumour, will respond to chemo)
N-myc amplification (nuclear transcriptional regulator of a number of critical genes)
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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FISH of Amplification of Oncogenes

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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HER-2 amplification in breast cancer

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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Clinical significance of HER-2 amplification

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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Where is the HER-2 gene located?

Chromosome 17

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Clinical significance of HER-2 amplification Diagram

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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HER-2 Targeted Therapy

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

HER2 and EGF meaning

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

Activation of oncogenes: Over expression of gene

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

Activation of oncogenes: Point mutations

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)

How do chromosome translocations activate proto-oncogenes ?

(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)

Myc translocations in Burkitts Lymphoma

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)

Significance of Myc translocation in Burkitts Lymphoma

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

Tumour Suppressor Genes

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

Tumour Suppressor genes Accelerators vs Brakes

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

Tumour suppressor Gene diagram

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

Retinoblastoma

“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)

Apoptosis - Programmed Cell death

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)

Genes which affect apoptosis

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

Pathways of Apoptosis

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

Summary: Genes in cancer

Oncogenes
- Dominant acting
- Promote cell growth
Tumour suppressor genes
- Loss of activity
- Inhibit cell proliferation
Genes involved in apoptosis

Multistep process

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

Epigenetic changes in cancer

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

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

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

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

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

What is the clinical relevance Cycle

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

Cancer Therapies that target oncogenic proteins

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

Chronic Myeloid Leukaemia (CML)

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

The Philadelphia Chromosome:

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

Bcr-Abl as a Therapeutic Target

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

Imatinib (glivec) 5 year data

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

Chronic Myeloid Leukaemia

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

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Genes and Cancer Flashcards

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