Flashcards in MOD - 10 Deck (56):
Causes of cancer
The cause of neoplasia is multifactorial. What does this mean? Give some examples:
It means that a combination of intrinsic host factors (heredity, age and gender (especially hormonal)), and extrinsic factors (environment and behavioural) account for cancer risk.
What has caused much of the increased cancer incidence over the last century?
Prolonged lifespan - age is a strong intrinsic factor that accounts for cancer risk.
About 30% of cancer deaths are due to the five leading behavioural and dietary risks. What are they?
1. High body mass index
2. Low fruit and vegetable intake
3. Lack of physical activity
4. Tobacco use
5. Alcohol use
Which behavioural/dietary factor accounts for approximately 25% of all cancer deaths?
Where has the evidence about cancer risks come from?
Epidemiological and animal studies.
How much of a population's cancer risk is caused by extrinsic factors?
What three lesson about carcinogenesis did epidemiological studies into workers in the dye industry who were exposed to the carcinogen, 2-napthylamine?
1. There is a long delay (sometimes decades) between carcinogen exposure and malignant neoplasm onset
2. The risk of cancer depends on total carcinogen dosage
3. There is sometime organ specificity for particular carcinogens e.g. 3-napthylamine causes bladder carcinoma.
Why is chemical exposure in an industrial setting more important for considering cancer risk than that in a domestic setting?
Cancer risk is dependent on the dose of carcinogen you are exposed to. This is often much higher in an industrial setting (e.g. asbestos, coal, tars, vinyl chloride), though smoking is an exception as high levels can be experienced at home.
In animal experiments is has been shown that the sequence in which carcinogens are administrated is critical. Explain why this is the case:
Some chemical carcinogens, called initiators, must be given first followed by a second class of carcinogens called promoters. This is because initiators are mutagens while promoters cause prolonged proliferation in target tissues. This culminates in monoclonal expansion of mutant cells.
What did the Ames test show?
That initiators are mutagens while promotors cause prolonged proliferation in target tissues.
How does a germline mutation differ from sporadic mutations in generating a monoclonal population of mutant cells?
Germline mutations skip the sporadic stages of initiation and promotion, as by their nature all cells in the body inherit the germline mutation. They therefore get a "head start".
List some classes of mutagenic chemical carcinogens (initiators):
1. Polycyclic aromatic hydrocarbons
2. Aromatic amines
4. Alkylating agents
5. Natural products: aflatoxin (fungi), asbestos (fibrous rock).
How are chemicals that are classified as pro-carcinogens, turned into carcinogens?
They are converted to carinogens by cytochrome P450 enzymes in the liver.
What are 'complete carcinogens'?
Carcinogens that act as both initiators and promotors.
How far does UV light penetrate?
No farther than the skin.
What is radiation? Is it mutagenic?
A type of energy that travels through space. Some forms of radiation are mutagenic.
What is ionising radiation? List some types of ionising radiation:
Radiation that strips electrons from atoms. X-rays and nuclear radiation (alpha-, beta- and gamma- particles) are forms of ionising radiation.
What are the two main main forms of radiation that we are exposed to?
1. UV radiation - sunlight (exposed daily)
2. Ionising radiation: background radon radiation and from medical tests.
What does ionising radiation do to DNA?
It damages DNA bases and causes single and double stranded DNA breaks.
What are the two main ways in which infections are carcinogenic?
1. Directly - affect genes that control cell growth
2. Indirectly - cause chronic tissue injury.
How is chronic tissue injury carcinogenic?
1. The resulting regeneration acts as a promotor for existing mutations
2. Regeneration causes new mutations from replication errors.
Give an example of an infection which directly affects genes that control cell growth:
HPV (human papilloma virus) expresses the proteins E6 and E7 which inhibit p53 and pRB respectively. Both these proteins are important in regulating cell proliferation. It is associated with cervical cancer, as well as some cancers of the vulva, vagina, penis, anus, and oropharynx.
How is hepatitis B and C carcinogenic?
They cause cancer indirectly by causing chronic liver cell injury and regeneration.
Name a bacteria that is carinogenic and its mechanism of action:
Heliocobacter pylori causes chronic gastric inflammation which can lead to gastric cancer.
Name a parasite that can cause cancer:
Parasitic flukes cause inflammation in bile ducts and bladder mucosa, increasing the risk of gastric. cholangio- and bladder carcinomas.
How does HIV infection predispose to cancer?
It suppresses the immune system and allows other potentially carcinogenic infections to occur.
Explain how the two-hit hypothesis explains the difference between retinoblastoma tumours occurring in families and those occurring in the general population:
1. Families: first hit delivered through germline and affected all cells in the body. The second hit was a somatic mutation.
2. General population: No germline mutations therefore requires both hits to be somatic mutations that occur in the SAME CELL.
What types of genes does initiation and promotion need to affect to lead to neoplasm?
Proto-oncogenes and tumour supressor genes.
What are oncogenes?
Abnormally activated versions of normal genes called oncogenes.
How many alleles of tumour suppressor genes need to be inactivated to lead to neoplasm?
Both - as they act like brakes on tumour growth.
How many alleles of proto-oncogenes need to be activated to lead to neoplasm?
What is the role of the Ras proto-oncogene?
It encodes a small G-protein that relays signals into the cell and eventually pushes the cell past the cell cycle restriction point.
What does a single mutatnt Ras oncogene do?
It is always active, ultimately producing a constant signal to pass through the cell cycle's restriction point.
What is the role of the Rb tumour suppressor gene? What happens if both alleles are mutated?
It restrains cell proliferation by inhibiting passage through the restriction point. Inactivation of both Rb allels therefore allows unrestrained passage through the restriction point.
What do proto oncogenes encode?
1. Growth factors (e.g. PDGF)
2. Growth factor receptors (e.g. HER2 - receptor for human epidermal growth factor).
3. Plasma membrane signal transducers (e.g. Ras)
4. Intracellular kinases (e.g. BRAF)
5. Transcription factors (e.g. MYC)
6. Cell cycle regulators (e.g. cyclin D1)
7. Apoptosis regulators (e.g. BCL2)
What do tumour suppressor genes encode?
Proteins in the same pathway but with anti-growth effects (e.g. TP53).
Mutation to which other class of genes (not TS or PO genes) can predispose to cancer?
DNA repair genes
What is Xeroderma pigmentosum? What causes it?
It is an inherited cancer syndrome which makes patients very sensitive to UV damage and they develop skin cancer at a very young age. It is autosomal recessive and caused by mutations in 1 of 7 genes that affect DNA nucleotide excision repair.
What is hereditary non-polyposis colon cancer (HNPCC) syndrome? What causes it?
It is an autosomal dominant syndrome which is associated with colon carinoma. The germline mutation affects one of several DNA mismatch repair genes.
Familial breast carcinoma is associated with which two genes? What is the role of these genes?
BRCA1 or BRCA2 genes. These are important for repairing double-stranded DNA breaks.
What is the effect on the genome of mutations to genes involved in nucleotide excision repair?
What is the effect on the genome of mutations to genes involved in mismatch repair?
What is the effect on the genome of mutations to genes involved in double strand break repair?
What are caretaker genes?
A class of tumour suppressor genes which maintain genetic stability.
How many mutations are required to make a malignant neoplasm?
Most malignant cells require alterations affecting a combination of multiple TS genes and proto-oncogenes. The exact number in a fully evolved malignant neoplasm (undergone initiation, promotion and progression) is unknown but thought to be approximately 10 or less.
What is cancer progression?
The steady accumulation of multiple mutations.
What is the adenoma-carcinoma sequence?
It is a sequence of steps (early adenoma, late adenoma, primary carcinoma and metastaic carcinoma) that occur in the development of colon carcinoma which are characterised by the accumulation of mutations and typically takes decades.
What are the 6 hallmarks of cancer?
1. Self-sufficiency in growth signals
2. Resistance to growth stop signals
3. No limit on the number of times a cell can divide (cell immortalisation)
4. Sustained ability to induce new blood vesels (angiogenesis)
5. Resistance to apoptosis
6. The ability to invade and produce metastasis (specific to malignant neoplasms)
What is an enabling characteristic of cancer?
Give an example of a molecular alteration seen in cancer that leads to the hallmark feature 'self-sufficiency in growth signals':
HER2 gene amplification in breast cancer. This encodes a receptor for human epidermal growth factor and therefore makes cells hypersensitive to low levels of this growth factor.
Give an example of a molecular alteration seen in cancer that leads to the hallmark feature 'resistance to anti-growth signals':
CDKN2A gene deletion (cyclin dependent kinase inhibitor) which causes melanoma.
Give an example of a molecular alteration seen in cancer that leads to the hallmark feature 'grow indefinitely':
Telomerase gene activation. This occurs in most cancers.
Give an example of a molecular alteration seen in cancer that leads to the hallmark feature 'induce new blood vessels (angiogenesis)':
Activation of VEGF (vascular endothelial growth factor) expression. This occurs in most cancers.
Give an example of a molecular alteration seen in cancer that leads to the hallmark feature 'resistance to apoptosis':
BCL2 (B cell lymphoma 2) gene translocation. This gene regulates apoptosis, This occurs in lymphoma.