1
Q
What is another name for ‘causes of cancer’
A
Carciogenesis
2
Q
What are intrinsic risks of cancer
A
- Age (old age)
- Sex (hormonal factors)
- Heredity (penetrance and frequency factors)
3
Q
What are extrinsic risks of cancer
A
- Environment and lifestyle
- High body max index
- Low fruit and vegetable intake
- Lack of physical activity
- Tobacco use
- Alcohol use
4
Q
Describe how chemicals can form a field of cancer cells
A
- Need initiators (mutagenic chemical carcinogens) and many promoters for carcinogen to develop
- Ames test shows that initiators are mutagens while promotors cause prolonged proliferation in target tissues
- Need promotors to form a field of mutagenic cells (progression)
- A germline mutation occurs fast as it differentiates into many cells
5
Q
Distinguish between pro-carcinogens and complete carcinogens
A
- Pro-carcinogen - only converted to carcinogens by the cytochrome P450 enzymes in the liver
- Complete carcinogens - act as both initiators and promotes
6
Q
Which radiation are we exposed to and how does it cause cancer
A
- Ionising radiation strips electrons from atoms (alpha, beta, gamma, x-rays)
- Nuclear radiation includes alpha, beta and gamma
- UV radiation most important as everyday exposure leads to risk of skin cancer
- Radon exposure and medical tests cause ionising radiation
- Damage DNA directly or indirectly by generating free radicals
- Direct DNA damage - altered base, single/double strand DNA breaks
7
Q
Explain how infections cause cancer
A
- Directly affect genes that control growth
- HPV produce proteins (E6, E7) which directly affect cancer producing genes
- E6 inhibit p53 to prevent apoptosis
- E7 inhibit pRb to allow free entry into cells cycle
- Strongly linked to cervical carcinoma
- HPV produce proteins (E6, E7) which directly affect cancer producing genes
- Indirectly cause chronic tissue injury, where the resulting regeneration acts either as a promoter for any pre-existing mutation or causes new mutation from DNA replication errors
- Hepatitis B and C cause chronic liver cell injury and regeneration - potential for mutation
- Bacteria and parasites can also indirectly lead to neoplasms
- Helobacter pylori causes chronic gastric inflammation
- Parasitic flukes cause inflammation in bile ducts and bladder mucosa - increase risk of gastric and bladder carcinomas
- Reduced immunity - HIV indirectly lowers immunity and allows potentially carcinogenic infections to occur
8
Q
What is the two hit hypothesis
A
- Inherited predisposition to neoplasia can occur through germline mutations
- First hit delivered through germline and affects all cells in the body
- Second hit is a somatic mutation
- Eg. Retinoblastoma - autosomal dominant
- For sporadic mutations, no germline mutation so requires both hits to be somatic mutations on the same cell (rarer)
9
Q
Describe the actions of proto-oncogenes and tumour suppressor genes on neoplasm growth
A
- Tumour suppressor genes inhibit neoplastic growth
- Need 2 hits to form neoplasm
- One gene can still make protein to stop abnormal growth
- Both alleles need to be inactivated
- Oncogenes enhance neoplastic growth and abnormally activated versions are proto-oncogenes
- Only 1 hit needed
- One gene will cause over proliferation of gene
10
Q
What is the role of caretaker genes
A
- Caretaker genes - tumour suppressor genes that maintain genetic stability
- Genetic instability leads to high mutation rate
- Chromosome segregation during mitosis can be abnormal in malignant cells and cause genetic instability
11
Q
What are examples of proto-oncogenes
A
- Growth factors
- Growth factor receptors
- Plasma membrane signal transducers - RAS
- Intracellular kinases
- Transcription factors
- Cell cycle regulators - cyclin D1
- Apoptosis regulators
12
Q
Outline how RAS can act as a proto-oncogene
A
- RAS oncogenes encodes a small G protein that relays signals into the cell that eventually pushes the cell past cell cycle restriction point
- RAS proto-oncogene undergoes GDP-GTP switch which activates cyclin D to bind to CDK
- Inhibits Rb gene to allow cell to enter cell cycle
13
Q
What are examples of tumour suppressor genes
A
- Rb genes restrains cell proliferation by inhibiting passage through restriction point
- Inactivation of both RB alleles needed to allow unrestrained passage through restriction point
- P53 also acts a tumour suppressant gene which activates apoptosis
14
Q
Describe the inheritance of xeroderma pigmentosum
A
- Due to mutations in DNA repair genes
- Inherited cancer syndrome with germline mutations affecting DNA repair
- Autosomal recessive
- Mutation in any 1 of 7 genes that affects DNA nucleotide excision repair (NER)
- Patients very sensitive to UV damage and develop skin cancer at young age
- Leads to nucleotide instability
15
Q
Describe the inheritance of hereditary non-polyposis colon cancer (HNPCC) syndrome
A
- Autosomal dominant
- Associated with colon carcinoma
- Germline mutation affects 1 or several DNA mismatch repair genes
- Leads to microsatellite instability
16
Q
Describe the inheritance of familial breast carcinoma
A
- Associated with either BRCA1 or BRCA2 genes important in repairing double strand DNA breaks
- Mutations also found in sporadic malignant neoplasms
- Leads to chromosomal instability
17
Q
Explain the adenoma-carcinoma sequence
A
- Eg. Colonic adenoma leads to colon carcinoma
- Mutations accumulate from early adenomas -> later adenomas -> primary carcinomas -> metastatic carcinomas
- Steady accumulation of multiple mutations called progression
18
Q
What are the 3 main steps for cancer to evolve
A
- Cancer evolves by initiation and promotion to progression
- Number of mutations needed to fully evolve malignant neoplasms unknown but <10
19
Q
What are the 6 hallmarks of cancer + 1 enabling feature
A
- To become a fully evolved malignant neoplasms, it needs to alter its growth control
1. Self sufficiency in growth signals
2. Resistance to growth stop signals
3. No limit on number of times a cell can divide (override telomere)
4. Sustained ability to induce new blood vessels (angiogenesis)
5. Resist apoptosis
6. Ability to invade and produce metastases - Genetic instability regarded as enabling characteristic
20
Q
Describe the overall process of carciogenesis
A
- Somatic cells are exposed to environmental carcinogens (chemicals, radiation, infections) that are either initiators or promoters
- Cumulates in a monoclonal population of mutant cells
- In 5% of cancers, inherited germline mutation can be present
- Some clones harbour mutations affecting a proto-oncogene or a tumour suppressor gene whose protein transcripts play crucial roles in cell signalling pathways affected by ‘hallmark’ changes
- During progression, cells acquire further activated oncogenes or inactivated tumour suppressor genes
- After many years or decades, results in population of cells that have acquired a set of mutations that produces all the ‘hallmarks of cancer’
21
Q
Describe some occupations associated with the development of tumours
A
- Dye industry
- Asbestos exposure
- Depends on length of exposure to chemicals
2 - PP
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