Year 1 Cancer: a genetic disease Flashcards
What are some examples of inherited genetic mutations?
- BRCA1/2
- DNA repair genes (XP)
- RB1
- ATM
- APC
- P53
What are some examples of acquired mutations?
- Ras
- P53
- ATM
- epigenetics
What are some examples of external factors which can influence cancer?
- smoking tobacco
- alcohol
- diet
- exercise
- solar radiation
- ionising radiation
- industrial asbestos
- pharmacological chemotherapeutic agents
What are some examples of infections which can cause cancer?
- HPV
- Epstein Barr Virus
- Hepatitis B Virus
- Helicobacter Pylori and gastric adenocarcinoma
How can immunosuppression cause cancer?
- increased cancers in AIDs and transplant patients
What are the 3 types of mutations found in oncogenes?
- point mutations (Ras)
- chromosomal rearrangements (Bcl-2)
- gene amplification (HER2)
How does h-ras involve a point mutation?
- GGC to GTC, glycine to valine
- bladder cancer
- single nucleotide exchange
- activates oncogene
What is an example of a chromosomal translocation?
- c-myc translocation places gene under control of highly active regulator from Ig gene
- Burkitt lymphoma
- also Bcl-2
Where is Bcl-2 upregulated?
- anti-apoptotic protein
- chromosomal translocation
- leukaemias
- non-Hodgkin lymphoma
- small cell lung cancer
What is an example of gene amplification?
- HER2 (breast cancer)
- EGFR (small cell lung cancer)
overexpression of both
What mutations occur in p53?
- tumour suppressor gene
- point mutations
- missense
- single nucleotide substitution
- TF p53 can no longer bind to DNA
What mutations happen in ATM gene?
- DNA repair gene
- role in repair of DNA double strand breaks
- many point mutations
- DNA repair impaired and mutations accumulate in other genes
- cerebellar cells particularly affected = ataxia
What are susceptibility genes?
- inherited mutations in genes
- tumour suppressor genes
- oncogenes
- DNA repair genes
- cell cycle control genes
- genes stimulating angiogenic pathway
What is penetrance?
- proportion of individuals carrying a pathogenic variant who will manifest the disease
What is the significance of methylation in tumour suppressor genes?
- hypermethylation at CpG islands
- inhibits transcription of gene
- if tumour suppressor gene = no DNA repair = loss of tumour suppressor gene expression
- hypomethylation in 3’ untranslated regions = genomic instability = promotes translocation
What is the significance of DNMT3B?
DNA methyltransferase 3 beta
- expressed strongly in colon carcinoma cells
- intense expression in aggressive carcinomas
- high methylation = highly aggressive carcinomas
How is DNA damaged?
- replication errors in S phase
- spontaneous damage altering base sequences
- mutagenic damage (endogenous and exogenous)
What are examples of endogenous mutagenic DNA damage?
indirect acting carcinogens which require metabolic activation:
- polycyclic aromatic hydrocarbons
- alcohol
What are some examples of exogenous mutagenic DNA damage?
direct acting carcinogens:
- oxygen species
- chemical mutagens
- x-rays
- UV radiation
What are the causes of spontaneous DNA damage?
- proofreading errors
- deamination of bases
- depurination (linking purine A/G to deoxyribose removing base)
- depyrimidination
- oxidation
What can smoking cause?
double strand breaks
lots of carcinogens = polycyclic aromatic hydrocarbons
- formation of DNA adducts
- BP formed = benzopyrene (fused benzene rings)
- cytochrome p450 formed = ultimate carcinogen producing chemical species and highly reactive mutagenic DNA
- lung cancer
- BPDE forms adduct with guanosine in lung epithelial cells
How can DNA adducts form in oral and oesophageal cancers?
- acetaldehyde break down forms deoxyguanosine and converts to weak mutagen (DNA adduct)
- then converts to stronger mutagen
What can radiation cause?
- indirect = creation of free radicals which damage bases/break DNA backbone
- direct = alpha/beta particles or x-rays create ions which break sugar phosphate backbone = pyrimidine dimers
What are some examples of cancers with pyrimidine dimers?
- melanosomes
- basal cell carcinomas
What causes XP?
- defect in human nucleotide excision repair
What are the symptoms of XP?
- light sensitive
- risk of sunlight induced cancer
- neurological abnormalities
What is the difference between non-melanoma and cutaneous melanoma?
- non melanoma = basal cell and squamous cell skin cancer at UV exposed sites
- cutaneous melanoma (melanocytes)
How can viruses cause cancer?
- HPV -> cervical cancer (sex)
- Epstein Barr Virus -> Burkitts Lymphoma, Hodgkins Lymphoma (saliva/blood/transplants)
- leukaemia virus type 1 -> Adult T cell leukaemia (mother to child, sex, blood transfusion)
- Hep B and C -> hepatocellular carcinoma (blood trans, organ trans, needles)
- H. pylori -> gastric adenocarcinoma via indirect inflammatory effects on gastric mucosa and direct epigenetic effects on cells
- schistosomiasia -> squamous cell and transitional cell bladder cancer
