What are the effects of maternal/paternal age on genetic risks of disease?
Higher with age as they have more time to acquire mutations and so can pass them on to their offspring.
What are the hallmarks of cancer?
- Dysregulated growth
- Autologous pro-growth signaling
- Insensitive to anti-growth signaling
- Evasion of apoptosis
- Limitless replication
- Sustained angiogenesis
- Invasion/metastasis
Caused by unstable genomes of cancer cells so they can keep acquiring mutations
What are tumour suppressor genes?
They regulate cell division and a mutation in them is known as a loss of function mutation.
What are proto-oncogenes?
They stimulate growth, make growth factors, TF and tyrosine kinases. When mutated into oncogenes they can override apoptosis. A mutation in them is known as a gain of function mutation.
What does a polyclonal tumour mean?
Genetically heterogenous – each cancer cell has different mutations, so the tumour is called polyclonal
What is the difference between mutations on a chromosome level and point mutations and give examples?
- Aneuploidy/translocation/microdeletion or insertions happens on a chromosome level
- Point mutations to base sequence – silent mutations, missense (change to amino acid), nonsense (stop codon)
Passenger vs driver mutations
- Driver mutation – initial mutation causing cell to become cancerous and every cell derived from it will have the mutation (same in people)
- Passenger mutation - mutations that have no effect in providing a growth advantage and do not lead to cancer (different in all people)
Somatic vs germline mutations
Germline - mutation in gametes and are passed onto offspring
Somatic - mutations in body cells
What is Knudson’s two hit hypothesis?
Two tumour suppressor genes need to be mutated (one for protooncogenes)
Hit 1 reduces transcription but is insufficient to cause a phenotypic effect
Inactivation of second allele causes total loss of transcription of that gene and hence leads to malignant potential
Sporadic and familial retinoblastoma
Either one mutation is inherited or sporadically emerged and then a second hit is required in order for it to develop.
Retinoblastoma: eye cancer affecting both eyes particularly in the young
What is loss of heterogeneity and how can it be detected?
Caused by nonsense or deletion mutations resulting in the loss of one gene or more.
One chromosome has one base whilst the other has another, so they overlap – snip. If there is deletion in a large area of a chromosome the array would not show any snips showing missing areas- used to be used for mapping earlier to see any missing genetic material.
What are BRCA1/2 mutations?
How do inherited mutations in BRCA1/2
genes influence risk of breast and ovarian cancer?
- Germline mutations cause 2-4%
- Earlier onset
- High risk of developing cancer by 90
- Increased risk of ovarian cancer
- Men with BRCA2 have a risk of getting breast cancer
- BRCA is a DNA repair gene – homologous recombination so cuts out damaged areas and replaces them
- Private mutations – many families affected have different mutations in the large gene so it is very hard to find the mutation in screening
What is FAP (familial adenomatous polyposis)?
- Inherited condition leading to colorectal cancer
- Each polyp has a chance of becoming cancer
- Colon is replaced by polyps
- 100% chance developing cancer but very rare
- Normally dominant – APC gene (TSG) chromosome 5
What is Lynch Syndrome (HNPCC)?
- Most common inherited colorectal cancer
- High risk of developing cancer
- Risk of other cancers like ovary, brain and skin
- Caused by DNA mismatch gene mutation that replace point mutations by snipping out and replacing wrong base
What is the management for patients with inherited cancer syndromes?
• Positive family history identified and genetic counselling
• If they have mutation, they may have surveillance so mammograms
• Chemoprevention
• Bowel removed if mutation causing FAP
(Some families have family history but no mutation in BRCA so maybe polygenic)
How can the causes of polygenic cancer be explored?
GWAS – genomes are compared on large scale (patients and control), SNPs are looked at to see the risk, identifies possible candidate genes, not causal, small individual effect
Transcriptome Chips/ mRNA array – proteins and mRNA looked at. High amounts of proteins may be present indicating a pathway is unregulated– but cause or effect
What is a cytogenic mutation?
Cytogenetic mutation – change to chromosome structure or number, important in all cancers, driver. Important in haemotological cancers
What are the types of leukaemia?
Leukaemia - acute and chronic
Acute is divided into myeloid and lymphoblastic
Chronic is divided into myeloid and lymphocytic
Chronic myeloid leukaemia
- Long term over production of granulocytes
- Common
- Middle age/elderly
- Chronic phase, accelerated phase, blast crisis (fatal)
- Anaemic, bleeding gums and nose, infections
- Philadelphia chromosome – fusion translocation of 9 and 22
- BCR and ABL1 fusion protein – acts as a tyrosine kinase which is involved in cascading
Acute myeloid leukaemia
- FAB M3 – medical emergency, haemorrhage, DIC (widespread blood clot formation in small vessels)
- FAB M5 (rare)– hepatomegaly (large liver), splenomegaly, gum infiltration, lymphadenopathy (lymph node disease and abnormalities)
- AUER rods in the cytoplasm
What is pharmacogenomics and give examples of where it can be used?
- Influence of genes on drugs
- Identify which chemotherapies will work on patients and means they avoid useless therapy
- Presence/ absence of mutations looked for
- KRAS test with cetuximab for colorectal cancer - KRAS mutation = less likelihood of response
- EGFR test with gefitinib for non-small cell lung cancer - EGFR mutation = greater likelihood of response
How can translocations lead to cancer?
Translocation - parts of different chromosomes undergo a reciprocal swap.
The translocation gives rise to two new chromosomes with abnormal morphology.
If there were genes at the breakpoint of the chromosomes, then the point at which the new junction is formed, a new gene may be formed. So this leads to the production of a new protein which could potentially have oncogenic properties.
How can IMATINIB be used to treat CML?
Imatinib blocks the ATP binding site of tyrosine BCR-ABL1 molecule rendering it inactive which ultimately leads to cell death. It kills CML cells only not normal cells as only present in cancer cells.
Some patients may develop resistance to imatinib but there is a second like TKI (Tyrosine Kinase Inhibitor) so monitoring is important in disease management.
How is disease quantified for CML?
Cytogenetics - look at the chromosomes themselves and count the number of cells with the chromosomal abnormality which is characteristic of CML. This can only be used in the first 6-12 months because it has a low resolution. It is laborious.
FISH (Fluorescence in situ Hybridisation) - apply fluorescently labelled probes to the genes at the break point. There is a coloured probe for the BCR and a different coloured probe for ABL1. You look for a fusion of the two colours. This has higher resolution. When the disease drops to less that 1%, something more sensitive is needed.
RT-qPCR (Reverse Transcriptase Quantitative PCR) - measure of the amount of gene transcript of BCR-ABL1 in peripheral blood. You hope not to detect any transcript whatsoever - many patients achieve this after 18-24 months.
