Lecture 4- Cancer Flashcards
Why do genetic changes cause cancer?
The resulting protein changes activate signal transduction pathways which lead to a selective advantage for the cell
What are the commonly affected pathways in cancer?
- cell cycle
- proliferation
- apoptosis
- adhesion
What are the three different types of point mutations?
1) Silent mutations: change in base but the new triplet code, codes for the same aa and you don’t get a change in protein structure
2) Missense mutation: change in codon= different as= different protein structure
3) Nonsense mutation: change in codon which results in STOP codon= truncated protein
What are the functions of tumour suppressor genes?
- regulate cell division
- DNA damage checkpoints (damage= no division)
- apoptosis if damaged
- DNA repair
What are the functions of proto-oncogenes?
Promote growth and proliferation
- growth factors
- transcription factors
- tyrosine kinases
Are TSG’s dominant, recessive or co-dominant?
Recessive
What are the consequences of a mutated tumour suppressor gene?
- Defective growth-inhibiting protein
- uncontrolled cell division
What is the two hit hypothesis?
Need to have two mutated TSG alleles to give cells the selective advantage
What does Hit1 of the two hit hypothesis cause?
- reduced transcript/ protein level
- insufficient to cause a phenotypic effect
What does hit 2 of the two hit hypothesis cause?
- total loss of transcription
- malignant phenotype
What is haploinsufficiency?
- when a single hit causes at least a 50% reduction in the level of transcript/ protein to give the cell a selective advantage
What is the difference between familial and sporadic retinoblastoma?
Familial:
- born with one RB mutation (hit 1)
- acquire second somatic mutation (hit 2)
Sporadic:
- Acquire one somatic mutation (hit 1)
- then have second somatic mutation in the same cell (hit 2)
In a loss of heterozygosity what sort of mutations are the two hits?
Hit 1= point mutation on the gene in one of the alleles
Hit 2= large deletion removing the TSG in the other chromosome
What causes inherited cancers?
Inheritance of mutation in germline tissue, usually in TSG
In inherited cancer syndromes, the risk of cancer is high but not always 100%. Why?
Two hit hypothesis
- hit 1 is inherited
- hit 2 in the second allele has to be acquired to cause a phenotypic change
But people who have the one mutated allele have a higher risk of acquiring the second hit
Germline mutation in Which genes cause an inherited predisposition to breast cancer?
- what is the risk of developing breast cancer and what other type of cancer might it cause?
BRCA1 and BRCA2
- 60% risk developing breast cancer by the age of 90
- earlier average age of onset
- increased risk ovarian cancer and breast cancer in men (BRCA2)
What is the function of the BCRA1/2 genes?
Involved in DNA repair by a process called homologous recombination
Name two causes inherited predispositions of cancer. State their: - name - gene they affect - % risk of cancer
FAMILIAL ADENOMATOUS POLYPOSIS (FAM)
- APC gene (cell division)
- 100% lifetime risk of cancer
LYNCH SYNDROME (HNPCC)
- MLH1/2 (DNA repair)
- 80% risk of colorectal cancer
How would you manage a patient for inherited cancer syndromes?
1) check family history
2) If FH is positive- offer genetic screening/ counselling
3) If mutation is positive- surveillance, prophylactic surgery, chemoprevention
How can you explore the causes of polygenic cancers?
GWAS studies (genome wide association studies)
What are cryogenic changes?
- changes in chromosome structure and number
- can be causal or accumulate
- translocation, deletion and duplication
How can translocations cause cancer?
- two genes fuse
- new chromosome could code for oncogenic proteins
What are cytogenetic analyses?
The observation of the morphology and number of chromosomes
Why are cytogenic analyses mainly used for haematological malignancies?
1) Leukaemia genomes are more stable than those of solid tumours- easier to pinpoint pathogenetic change
2) Easier to perform cytogenetics on haematopoeic circulating cells
What causes myeloid leukaemias?
Malignancy of monocytes and neutrophils
What happens in Chronic Myeloid Leukaemia?
Overproduction of mature granulocytes
What causes Chronic Myeloid Leukaemia?
Translocation between Chr 9 and Chr 22 –> BCR -ABL1 gene fusion in the changed Chr 22 which is oncogenic.
What is another name for the newly formed Chr 22 in CML?
A philadelphia chromosome
What is the BCR-ABL1 gene translate to produce?
BCR-ABL1 groin tyrosine kinase which causes CML
What drugs is administered to people with CML as part of targeted molecular therapy?
Imantinib
How does Imantinib work?
- Blocks the ATP binding site of tyrosine BCR-ABL1 molecule –> cell death
- kills CML cells
What might be offered to patients who become resistant to Imantinib?
Second line Tyrosine Kinase Inhibitor
Why is cytogenetics insufficient for monitoring the progress of CML?
- only used in the first 6-12 months
- low resolution
- laborious
What are the alternate methods of monitoring CML?
- FISH (Fluorescence in situ Hybridisation)
- RT-qPCR ( Reverse Transcriptase quantitative PCR)
How does FISH work?
- apply fluorescently labelled probes to the genes at break point
- coloured probe for BCR and another colour for ABL1
- look for fusion of colours= CML
How does RT- qPCR work?
- measures the amount of gene transcript of BCR-ABL1 in the blood
- shouldn’t detect any transcript at all
When might you need to swap therapy for CML?
- absence of cryogenic response by 12 months
- > 10% RT-qPCR at 3 months
- loss of RT-qPCR negativity = relapse imminent= change therapy
What is APML?
Acute Promyelocytic Leukaemia= abnormal accumulation of immature granulocytes called promyelocytes
What causes APML?
- balanced chromosome translocation
- Retinoic Acid Receptor Alpha (RARA gene) on Chr 17 and Promyelocytic Leukaemia (PML) gene on Chr 15 (t(15;17)(q22;q12)
What is the normal function of the RARa gene?
- a nuclear receptor which binds to vitamin A and then to DNA and regulates the transcription of multiple genes
What happens to the RARa gene when it fuses with the PML gene?
- Change in shape of receptor
- binds to strongly to DNA
- Gene is silenced- blocks transcription
- Cell proliferates
What is the treatment for APML?
All Trans Retinoic Acid (ATRA) which is a vitamin A derivative
- doesn’t kill cells
- APML patients have to take ATRA for the whole of their lives
How does ATRA prevent APML?
- ATRA binds to DNA with higher affinity than abnormal RARa
- RARa dissociates from DNA
- DNA no longer silenced
Name the four cancers caused by translocations
- Burkitt’s Lymphoma
- Philadelphia, CML (BCR- ABL1)
- APML (RARa- PML)
- Ewlings sarcoma
What is pharmacogenomics
A branch of pharmacology which deals with the influence of genetic variation on drug response
Give three examples of pharmacogenomics in use. State the test, drug and type of cancer
1) KRAS- etuximab- colorectal cancer (response less likely )
2) EGFR- gefitnib- non-small cell lung cancer (response more likely)
3) BCR-ABL1 T315I - dasatinib- CML (response less likely)
