11. Cancer genetics 3: DNA repair genes Flashcards
1. Cancer is a genetic disease 2. DNA repair genes and consequences 3. Carcinogen metabolism
What are carcinogens?
DNA altering chemicals
What kind of progression is cancer?
step wise
How many cancer causing genes are there?
around 700 genes which is 2-3% of all human genes
How many hits do oncogenes need?
generally only 1 mutated allele is needed to initiate cancer
How many hits do tumour suppressor genes need?
need mutations in 2 alleles to contribute to cancer
What are 3 statements that describe Knudson’s 2-hit theory?
- it underpins the identification of tumour suppressor genes
- it applies to the development of familial cancers
- it applies to the tumour that arise from somatic mutations
Why study cancer genetics: family planning
It is used to predict the likelihood the offspring will have the mutation and gives people more information when they are starting a family
Why study cancer genetics: prophylactic prevention
Removal of the at risk tissue like a mastectomy when the patient has a BRCA1/2 mutation
Why study cancer genetics: insights into aetiology
It helps provide insight into the cause of the cancers in general and of a specific cancer. Applies to both sporadic and inherited cancers
Identification of predisposing genes: linkage analysis
- Used to trace the pattern of disease through high risk families
- Use these as a way to identify genetic markers and co-inherited regions
- Use the link between these markers and cancer
Identification of predisposing genes: karyotypes
Use to see the chromosomes and identify:
1. translocations
2. large deletions
3. aneuploidy
4. polyploidy
5. truncations
Identification of predisposing genes: allele loss studies to find loss of heterozygosity
- normally 2 bands for 2 different alleles
- only 1 band can indicate a loss of 1 allele and therefore heterozygosity
Identification of predisposing genes: whole genome sequencing
- taking advantage of recent technology
- sequence the whole genome and map to a reference genome
- has been used to identify TSGs like B-raf
What are primary causes of cancer?
- they have direct involvement in the development of cancer
- oncogenes
- TSGs
What are indirect causes of cancer?
- Genes that are not directly involved in causing cancer but they play a role
- DNA repair genes that without function mutations will accumulate
- Carcinogen metabolism genes which convert metabolite to carcinogens or visa versa
Why are DNA repair genes important in cancer development?
- when they work properly they can repair DNA damage and prevent them becoming mutations
- aid cell survival
- If the repair is unsuccessful it kills the cell to prevent passing on mutations
- If these repair mechanisms don’t work that mutations accumulate and contributes to cancer
What are the ways DNA can be damaged?
- Reactive oxygen species
- UV light
- Smoking and other bulking DNA products
- modifications of bases like alkylation
- DNA replication mistakes
How can DNA damage be repaired?
- nucleotide excision repair
- base excision repair
- Mismatch repair
When does DNA need to be repaired?
before replication takes place and the cell proliferates
What happens if DNA is not repaired properly?
Accumulation of mutations
What can DNA damage fingerprinting help do?
- help identify what caused the cancer
- currently over 97 distinct signatures for different carcinogens
What is Ataxia telangiectasia?
- A rare, autosomal recessive disease caused by ATM mutation
- effects the cerebellum so effects co-ordination - ataxia
- telangiectasia = dilated capillaries
- immune deficiency
- highly sensitive to ionising radiation like sunlight and X-rays
- risk of leukaemia and lymphoma
- Heterozygotes have increased cancer risk
What causes Ataxia telangiectasia?
Mutation in ATM
What is ATM?
- A protein that senses DNA damage especially dsDNA breaks
- Kinase activity
- ATM activates CHK2 to arrest the cell cycle in the S phase
- also activates p53 to arrest the cell cycle at the G1 checkpoint
What happens in cells with ATM mutations?
- cell cycle is not arrested and the mutations accumulate and are passed on to the daughter cells
- cellular catastrophe
- more dsDNA breaks
- mitotic catastrophe that leads to weird things like 3 daughter cells after mitosis
What is Xeroderma pigmentosa?
- A rare autosomal recessive disorder
- features include dwarfism, intellectual disability, blindness, deafness
- Severe UV sensitivity and early onset skin cancers, XP patients have exponential risk early in life
- mutations in genes involved in DNA excision repair so mutations accumulate over time
What is bloom syndrome?
- A DNA helicase deficiency due to mutation in BLM gene that helps in DNA helicase production
- not optimal DNA replication leading to more errors
What is Fanconi anaemia?
- Mutations in over 20 genes in the homologous recombination pathway
- each protein is involved in recruiting the others so if one is defective then the recruitment doesn’t happen and repair fails
- causes: anaemia, intellectual disability, skeletal abnormalities, leukaemia
What is an example of a Fanconi gene?
- BRCA 2
- Causes falcon anaemia, childhood tumours, ovarian cancer, breast cancer
- some genes are more important in predisposing to certain cancer like BRCA1/2 and breast cancer
What are microsatellite repeats?
- short repeated sequences in the DNA
- makes it harder for the cell to replicate and causes lots of errors
- located near coding regions
What is microsatellite instability?
- When the microsatellites are mis replicated caused by a deficiency in mismatch repair.
- very common in cancers
What is hereditary non-polyposis colon cancer?
- lynch syndrome
- autosomal dominant
- mutations in mismatch repair genes which cause errors in the DNA
- early onset colon cancer
- eg MLH1, MSH2, MSH6, PMS1, PMS2
What can mismatch repair defects cause?
TGFß receptor loss
what does TGFß receptor loss cause?
- truncated receptors caused by a frame shift mutation and a premature stop codon
- receptors are degraded
- TGFß cannot bind
- TGFß cannot prevent cell proliferation
- results in uncontrolled growth
What is the function of TGFß?
- inhibits cell growth by binding to its receptor
- TGFß receptor is a serine/threonine kinase receptor
Carcinogen metabolism: initiation
- starts the process of mutagenesis
- caused by a carcinogen
- irreversible cell damage
- this itself cannot cause cancer
Carcinogen metabolism: promotion
- supports the proliferation of the initiated cells
- can be reversible in the early stages
- you can only promote an initiated cell
Carcinogen metabolism: progression
- development of more malignant features
- more mutations
What can some carcinogens be?
both initiators and promoters
What are pro-carcinogens?
Chemicals/compounds that need to be metabolised by the body to become carcinogens
What is an example of an enzyme that metabolises carcinogens?
- cytochrome P450 enzymes like CYP2D6
- usually hydroxylate bases
- people with more of these enzymes have higher risk of some cancers suggesting they have a role in converting pro-carcinogens
