Lecture 5 Flashcards
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 (normally nonsense mutation)
Inactivation of second allele causes total loss of transcription of that gene and hence leads to malignant potential(normally deletion)
MUTANT TSG genes are typically recessive. I think this means that eg they are normally AA, after one hit, it becomes Aa (one becomes recessive but there is still one dominant allele that can produce TSG). Second hit then becomes aa.
oncogenes are normally dominant, so one mutation will mean that it will show symptoms and cause problems
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)?
- a syndrome that increases the risk of developing 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)
