3 - Aetiology of Carcinogenesis Flashcards
Carcinogenesis
The process by which normal, healthy cells transform into cancer cells
Somatic mutation theory
- Cancers arise from mutations in individual cells, passed on through division
- Clinically observable cancer is result of accumulating multiple mutations
Mutator phenotype
An acquired increase in rate of mutation
What does first mutator acquisition relate to
- Increased cell division
- Abnormal DNA replication
- Damaged DNA repair mechanisms.
Lethal mutation
Disruptive in a manner that harms or kills the cell
Passenger mutation
Consequential, no selective advantage
Driver mutations
Provides a selective advantage
Multi step process of mutation
- Cancer causing mutations are cumulative but randomly ordered
- Mutation can occur in any cell at any time
- Most likely to occur during DNA replication
- Will only be passed on if cell divides
Stepwise mutations
- Results in heterogeneity between tumours in an individual with metastatic disease or within a single tumour
- Has implications for therapy (one cell with resistance survives treatment then replicates so cancer comes back resistant)
Examples of tumours co-opting existing cellular pathways
- VEGF disruption can change angiogenesis
- P53 disruption can interfere with apoptosis
- MAPK signalling can impact on tissue invasion, growth signals self-sufficiency AND proliferation
Selective pressures of tumours
- Immune system
- Tumour suppressor genes
- Microenvironment (e.g. anaerobic respiration under hypoxia)
Feedback loop of cancer
Less tumour cell death –> more proliferation –> more rounds of DNA replication –> more chance of passing mutations on –> more opportunity for mutation and instability
Proto-oncogenes typically are one of
- Cell division stimulators
- Differentiation blockers
- Apoptosis inhibitors
- Components of signalling pathways
- Growth factors.
How do proto-oncogenes become oncogenes
When expressed at increased levels, resulting from either:
- Amplification leading to more copies of the gene
- Translocation to a more active promotor
- Mutation resulting in a fusion protein with oncogene activity
How many oncogenes currently known
> 40
Examples of oncogenes
MYC and RAS
MYC
- Transcription factor
- Overexpressed/activated in >50% of human cancers
- Coordinates many cellular processes (e.g. angiogenesis)
- Proliferative arrest
- Blocks senescence and differentiation
MYC addiction
- Tumour survival often depends on high MYC
- Not sufficient alone for carcinogenesis
RAS
- GTPase signalling proteins
- 3 RAS genes
- RAS on/off activity is sped up by regulatory proteins
RAS regulatory proteins
- Guanine nucleotide exchange factors (GEF) catalyse exchange of GDP with GTP (RAS “switched on”).
- GTPase-activating proteins (GAP) catalyse hydrolysis of GTP to GDP (RAS “switched off”).
- Mutant RAS don’t allow GAP to coordinate hydrolysis (RAS is stuck ‘on’)
3 RAS genes
- KRAS, NRAS, HRA
- RAS mutants are 85% KRAS
RAS effects
- Cell survival and growth
- Transcription
- Cell cycle progression
- Cell migration
Tumour supressor genes
- “anti-oncogenes”
- Problem if these are knocked out
- Often requires both alleles being knocked out
- Hereditary susceptibility
- Often have suppressive or regulatory activity
Suppressive or regulatory activity of tumour suppressor genes
- Control proliferation
- Initiate apoptosis if DNA damage is detected
- Regulate adhesion i.e. stop metastasis
Large scale mutations
- Less common, usually happens during mitosis
- Chromosomal gain/loss (usually lethal)
- Translocation/duplication/deletion of large fragments
Chromosomal gain/loss
- Down syndrome (trisomy 21)
- Klinefelter syndrome (XXY)
Translocation/duplication/deletion of large fragments
- Philadelphia chromosome seen in CML
- D deletion syndrome seen in retinoblastoma
Philadelphia chromosome
Translocation between long arms of chromosomes 9 and 22
D deletion syndrome
Loss of long arm of chromosome 13
Small scale mutations
- Point mutations
- Proteins can still be made
- Very subtle differences
- May prevent one particular role
- Frame shift in reading frame
Carcinogenesis causes
Endogenous or exogenous (mainly)
Endogenous causes
- Spontaneous
- Random mistakes in DNA replication
- Chance increases with age
- Lifetime incidence of many cancers correlates with normal homeostatic cell division rates in that tissue
Exogenous causes
- Carcinogens causing cancer
- Mutagens cause genetic mutation
- Most carcinogens are mutagenic
Three main groups of carcinogens
- Chemical (e.g. alcohol)
- Radiological (e.g. UV, x-ray)
- Biological (e.g. viral, bacterial)
Mechanisms of action of environmental carcinogens
- Sources of carcinogen vary in their likelihood of causing cancer in broader or more restricted range of tissues
- Depends on site of exposure
- Exposure to higher amounts can allow chemical carcinogens to accumulate in other organs in concentration that can cause disease
Alcohol
- Increases risk of mouth, pharynx, larynx, oesophagus, bowel, liver, breast cancer
- Via blood stream, affects many tissues/organs around the body
Alcohol mechanisms of causing cancer
- Ethanol -> acetaldehyde by alcohol dehydrogenase (damages DNA & stops cells from repairing)
- Ethanol may also cause direct tissue damage to cells of mouth/throat
- Acts as a solvent for other carcinogens (e.g., from smoking);
- Increases level of hormones such as oestrogen (linked to breast cancer) or insulin.
How many annual cases of cancer in Aus are attributable to long term alcohol consumption
> 3,200
UV radiation
- 99% of non-melanoma skin cancers and 95% of melanoma caused by UV
- Sources (sun, sunbeds, sun lamps)
- UVA penetrates into dermis (Genetic damage to cells, photo-ageing, immune-suppression)
- UVB penetrates into the epidermis (Damages cells, responsible for sunburn -> melanoma)
- If damage isn’t repaired, cell may grow in uncontrolled way
Incidence of cancer due to radiation in Aus
> 13,000 new cases & >1,700 deaths annually
HPV
- 14 types can cause cancer (16 & 18 cause 70% of cancer)
- Chronic infection can lead to pre-cancerous lesions
- Host genome integration leads to higher risk
- Two HPV proteins strongly associated with cervical cancer
Risk factors of HPV
- HPV type
- Immune status
- Coinfection (e.g. herpes simplex, chlamydia)
Two HPV proteins strongly associated with cervical cancer
E6 and E7
E6
Inhibits p53 (normally induces apoptosis in response to cellular stress inc DNA damage and viral infection)
E7
Inhibits Rb (normally prevents cell division by blocking transcription factors)
Cancer mutational burden
- Different cancer types carry characteristically different levels of mutations
- Mutational signatures differ across cancer types
- Some represent different base substitutions evenly, whilst some are remarkably specific.
