Flashcards in Neoplasm 3 Deck (22):
What are the 5 leading caner risk?
About 30% of cancer deaths are due to the five leading behavioural and dietary risks: high body mass index, low fruit and vegetable intake, lack of physical activity, tobacco use, and alcohol use. Extrinsic carcinogens account for 85% of cancer risk and fall into 3 main categories: chemicals, radiation and infections, to be described next.
What is 2-napthylamine ?
2-napthylamine is an Industrial carcinogen used in the dye manufacturing industry that can lead to bladder cancer
What did studies about exposure to 2-napthylamine show?
• There is a long delay (sometimes decades) between carcinogen exposure and malignant neoplasm onset
• The risk of cancer depends on total carcinogen dosage
• There is sometimes organ specificity for particular carcinogens, e.g. 2-napthylamine causes bladder carcinoma.
What are initiators and promoters?
Chemical carcinogenesis involves initiation and promotion. Some chemical carcinogens, called initiators, must be given first followed by a second class of carcinogens called promoters. Initiators are mutagens while promoters cause prolonged proliferation in target tissues and are not mutagenic. This culminates in a monoclonal expansion of mutant cells.
Discuss some mutagenic chemical carcinogens (initiators)
Mutagenic chemical carcinogens (i.e. initiators) can be classified as polycyclic aromatic hydrocarbons, aromatic amines, N-nitroso compounds, alkylating agents and diverse natural products, e.g. aflatoxin, asbestos. Some of these chemicals are pro-carcinogens and are only converted to carcinogens by the cytochrome P450 enzymes in the liver.
What do you call carcinogens that act both as promoters and initiators
Carcinogens that act as both initiators and promoters are called complete carcinogens.
How can ionising radiation cause DNA damage?
Certain types of radiation are mutagenic. Ultraviolet (UV) light does not penetrate deeper than skin. Ionising radiation strips electrons from atoms and includes X-rays and nuclear radiation arising from radioactive elements. Radiation can damage DNA directly and also indirectly by generating free radicals. Ionising radiation damages DNA bases and causes single and double strand DNA breaks.
How can infections help to cause cancer?
Some infections directly affect genes that control cell growth. Others do so indirectly by causing chronic tissue injury, where the resulting regeneration acts either as a promoter for any pre-existing mutations or else cause a new mutations from DNA replication errors.
How does HPV cause cancer?
Human Papilloma virus (HPV), which is strongly linked to cervical carcinoma, is a direct carcinogen because it expresses the E6 and E7 proteins that inhibit p53 and pRB protein function respectively, both of which are important tumour suppressors.
How does Hep B and C cause cancer?
Hepatitis B and C viruses are indirect carcinogens that cause chronic liver cell injury and regeneration.
How does H-Pylori cause cancer?
Helicobacter pylori causes chronic gastric inflammation and parasitic flukes cause inflammation in bile ducts and bladder mucosa, increasing the risk for gastric, cholangio and bladder carcinomas respectively.
How does HIV cause cancer?
• Human Immunodeficiency virus (HIV) acts indirectly by lowering immunity and allowing other potentially carcinogenic infections to occur.
Describe the two hit hypothesis and how it was discovered from investigations into Retinoblastomas.
Inherited predispositions to neoplasia can occur through germline mutations. Retinoblastoma shows a dominant pattern of inheritance in some families. As well as running in families, this tumour occurred sporadically. In the 1970s Knudson postulated a two hit hypothesis to explain the differences between tumours occurring in families and those occurring in the general population. For familial cancers, the first hit was delivered through the germline and affected all cells in the body.
Explain the difference between tumour suppressor genes and proto-oncogenes and the number of them that must be mutated in a cancer?
Initiation and promotion lead to neoplasms when they affect proto-oncogenes and tumour suppressor genes. Because tumour suppressor genes act like brakes on tumour growth, both alleles must be inactivated, which explains why they need two hits, i.e. one for each allele. In contrast, genes that enhance neoplastic growth are known as oncogenes and are abnormally activated versions of normal genes called proto -oncogenes. Only one allele of each proto -oncogene needs to be activated to favour neoplastic growth.
Give an example of common oncogenes and Tumour supressor genes that are mutated in cancers
The first human oncogene to be discovered was RAS and this is mutated in approximately a third of all malignant neoplasms. The RAS proto - oncogene encodes a small G protein that relays signals into the cell that eventually pushes the cell past the cell cycle restriction point. Mutant RAS encodes a protein that is always active, ultimately producing a constant signal to pass through the cell cycle’s restriction point. In contrast, the RB gene restrains cell proliferation by inhibiting passage through the restriction point.
Give 7 examples of the types of genes that proto-oncogenes can encode?
1. Growth factors (e.g. PDGF)
2. Growth factor receptors (e.g. HER2)
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).
TS genes encode proteins in the same pathways but with anti -growth effects (e.g. TP53).
What causes xeroderma Pigmentosum?
Xeroderma Pigmentosum (XP) is due to mutations in DNA repair genes, it is autosomal recessive, is due to mutations in one of 7 genes that affect DNA nucleotide excision repair (NER). These patients are very sensitive to UV damage and develop skin cancer at a young age (nucleotide instability).
What causes Hereditary non-polyposiscolon cancer syndrome?
Hereditary non -polyposis colon cancer (HNPCC) syndrome, which is autosomal dominant, is associated with colon carcinoma and the germline mutation affects one of several DNA mismatch repair genes (Microsatellite instability).
What do the BRAC1 and BRAC2 genes encode?
Familial breast carcinoma is associated with either BRCA1 or BRCA2 genes that are important for repairing double strand DNA breaks.
Why do neoplasms have an accelerated mutation rate compared to normal cells, other than their fast growth rate
Genes that maintain genetic stability belong to a class of tumour suppressor genes called caretaker genes, various mutations of these genes can be found in sporadic malignant neoplasms (chromosomal instability). Chromosome segregation during mitosis can also be abnormal in malignant cells. Together, these alterations account for the accelerated mutation rate found in malignant neoplasms that is known as genetic instability.
What is progression?
Multiple mutations are required to make a malignant neoplasm. Most malignant tumours require alterations affecting a combination of multiple TS genes and proto -oncogenes. These mutations are acquired over decades. This steady accumulation of multiple mutations is called cancer progression. Therefore cancer evolves by initiation and promotion and finally by progression.