Oncogenesis Flashcards
What is cancer?
A term for diseases in which abnormal cells divide without control and can invade nearby tissues. Cancer cells can also spread to other parts of the body through the blood and lymph systems
What are the 4 main stages fo carcinogenesis?
- initiation
- promotion
- progression
- malignant conversion
What happens in the INITIATION of carcinogenesis?
interaction of carcinogen with DNA
What happens in the PROMOTION of carcinogenesis?
- selective growth advantage (free radicals)
- early pre-cancer (adenoma) reversible
What happens in the PROGRESSION of carcinogenesis?
- enhanced cell division
- later pre-cancer (late adenoma), reversible
What happens in the MALIGNANT CONVERSION of carcinogenesis?
- cancer, not reversible
Which tumour suppressor gene is reliant for colorectal cancer?
adenomatous polyposis coli (API)
expression associated with later stage tumour
What is a carcinogen?
substances and exposures that can lead to cancer
N.B chemo is also carcinogenic
What are the 3 types of carcinogens?
- chemical
- physical
- viral
What are examples of chemical carcinogen?
benzene acylating agents (chemo)
What are examples of physical carcinogens?
X-rays
UV light
alpha particles
What are examples of viral carcinogens?
- hep B
- HPV
What are examples of hereditary cancer predisposition syndromes?
Li-Fraumeni syndrome (TP53 loss of function)
Down’s syndrome (trisomy 21)
What are the 2 main types of physical carcinogens?
- ionising (gamma, X-rays)
- non-ionising (UV ligjht)
What are proto-oncogenes?
normal cellular genes which regulate cell growth and/or division and differentiation
What is an oncogene?
A porto-oncogene that has been activated by mutation or overexpression
What is an eg of a point mutation creating an oncogene?
point mutation creating K-RAS in lung cancer
What is an eg of a gene amplification creating an oncogene?
c-myc
breast cancer
What is an eg of a chromosomal translocation creating an oncogene?
creation of fusion protein
BCR-ABL (chronic myeloid leukaemia)
How many alleles/inheritance is required to mediate effects of an oncogene?
dominant effect
only one altered allele is needed to mediate pathogenic effects
What does the Her2/neu/ERBB2 gene encode?
part of the human epidermal GF receptor
How does the Her2 receptor function?
Her2 = tyr-kinase receptor
binding of GFs (e.g. EGF)
confirmational change to activate receptor
receptor dimerisation needed for function
What is the link between Her2 and cancer?
- HER2 is amplified in ~20% of invasive breast cancers
- associated with aggressive disease and poor prognosis
What is the nature of the Her2 gene dysfunction?
no point mutation in coding gene
OVEREXPRESSION of Her2 gene
resulting in high abundance of Her2 receptor on PM
What targeted therapies are available for Her2 tumours?
Monoclonal antibodies:
Trastuzumab (Herceptin) and Pertuzumab
Only effective in HER2+ cancers
These agents disrupt the dimerisation of the Her2 receptors that result in activation of the downstream signalling cascade
What is the BCR-ABL1 translocation contain?
BCR: protein acts as a guanine GEF for Rho GTPase
ABL1: protein tyrosine kinase receptor (activity is controlled by autophosphorylation = inhibition).
How does BCR-ABL1 mediate pathogenic effects?
BCR-ABL1 protein has constitutive/unregulated protein tyrosine kinase activity
- proliferation of progenitor cells in absence of GFs
- decreased apoptosis
- decreased adhesion to BM stroma
What kind of gene is ABL1?
Proto-oncogene encoding a cytoplasmic protein
What is the Philadelphia chromosome?
BCR-ABL1 translocation
Found in 95% of CML cases
What does presence of the Philadelphia chromosome indicate?
(BCR-ABL1 translocation)
- detection of minimal residual disease
What treatments can be used in BCR-ABL1 positive tumours?
drugs that specifically inhibit BCR-ABL1
e.g. Imatinib (inhibitor)
What are the Myc proto-oncogenes?
encode for transcription factors
What do pathogenic alterations in c-myc cause?
- gene retrovirus activation
- amplifications
- translocations
How are c-Myc oncogenes produced?
integration of viral DNA into the host genome
translocation adjacent to c-Myc
Overstimulaton at promoter
uncontrolled cell proliferation and so tumorigenesis
What are tumour suppressor genes?
encode proteins that maintain checkpoints and control genome stability
What mechanisms do tumour suppressor genes use to control the cell cycle?
- Repair of DNA damage (MLH1, BRCA1/2)
- Apoptosis (TP53)
What is the main function of tumour suppressor genes?
- inhibit replication
- Inhibit proliferation of damaged cells
What is Knudson’s two-hit hypothesis?
most LoF mutations that occur in tumour suppressor genes are recessive in nature
A second hit (homozygous recessive) is needed to disrupt gene function
What process favours the acquisition of DNA mutations?
KO of DNA repair function
usually of 1 or more genes
sequential process
What results from defects in DNA repair mechansims?
- genomic instability
- (accelerated) activation of oncogenes
- loss of tumour suppressor genes
What do tumour resulting from inherited defects in DNA repair genes imply about the mutational load?
high mutational load
i.e. due to the the 2-hit hypothesis and recessive nature of tumour suppressor genes
lots of mutations are needed to initiate tumour formation as a result
What is the function of the BRCA1/2 genes?
to repair double stranded DNA breaks
What proteins repair ssDNA breaks?
PARP proteins
Why do new Rx target PARP proteins for breast cancer?
PARPi = new Rx in BRCA1/2 carriers. Inhibit the repair of ssDNA breaks.
This means that there are no DNA repair mechanisms (dsDNA or ssDNA) and so cells die by apoptosis
What are the main types of PARPi?
- Olaparib
- Rucaparib
- Niraparib
- Talazoparib
What is the direct function of p53?
protein which works at the G1/S checkpoint
binds to p21 (a CDK inhibitor)
What tumour suppressor proteins work at the G1/S phase checkpoint?
- p53 (p21)
- Rb-E2F
What are the functions of p53?
- detects cellular stress, especially DNA damage
- induces G1/S and G2/M cell cycle arrest
- if this fails, apoptosis is triggered
How is TP53 implicated in cancers?
> 50% of cancers cause TP53 mutations
In some cancers, TP53 mutations correlate with pathological stage of cancer (can indicate later/more severe stage)
What is Li-Fraumeni syndrome?
mutations in TP53 causing increased risk for cancers
> 70% of families with this will have a mutation in TP53
Which cancers does Li-Fraumeni syndrome predispose you to?
- breast
- leukaemia
- lung
- pancreas
- sarcoma
- Wilms
- Gliobastoma
What is Wilms tumour?
nephroblastoma
rare kidney cancer, highly treatable
prevalent in children
What is RB1?
- tumour suppressor “gatekeeper”
- acts at G1/S phase transition, preventing cell cycle and growth until all criteria are met for it to proceed
- inactivated by phosphorylation
How is RB1 related to malignancy?
- malignant tumours of eye originating from the retina
- occurs in 1:20,000 childen
- 90% occur <5yo
- Rx: surgery and radiotherapy
- 98% cases cured
What is SPORADIC retinoblastoma?
(no FMHx)
- 60% of cases
- single tumour
- unilateral
What is FAMILIAL retinoblastoma?
- 30% of cases
- FMHx
- multiple tumours
- bilateral
What are the main challenges with oncogenesis?
cancer caused by accumulation of multiple mutations
tumour heterogeneity
diverse physiological pathways
tissue specificity
