Neoplasms 3 Flashcards
What accounts for cancer risk?
A combination of intrinsic host factors and extrinsic factors
Give 3 examples of intrinsic host factors that can account for cancer risk
Hereditary
Age
Gender (especially hormonal)
What are extrinsic factors for cancer risk related to?
The environment and behaviour
What is much of the increased cancer incidence over the last century due to?
Prolonged life span
What are the five leading behavioural and dietary risks for cancer?
High body mass index Low fruit and vegetable intake Lack of physical activity Tobacco use Alcohol use
What % of cancer deaths are due to the 5 leading behavioural and dietary risks?
30%
What is tobacco smoke alone associated with?
Approx. 1/4 of all cancer deaths
Where does most of the evidence about cancer risk come from?
Epidemiological and animal studies
How much of a populations cancer risk do extrinsic factors account for?
About 85%
What categories to extrinsic carcinogens fall into?
Chemicals
Radiation
Infections
Give an example of a industrial carcinogen
2-napthylamine
Where is 2-napthylamine used?
In the dye manufacturing industry
What do malignant neoplasms caused by 2-napthylamine show?
There is a long delay (sometimes decades) between carcinogen exposure and malignant neoplasm onset
The risk of cancer depends on carcinogen dosage
There is sometimes organ specificity for particular carcinogens
What does 2-napthylamine cause?
Bladder carcinoma
What does the dependance on dosage of carcinogens mean?
Industrial carcinogens and tobacco smoke are especially important
Give 3 examples of industrial carcinogens
Asbestos
Coal tars
Vinyl chloride
What is tobacco smoke associated with?
Bronchial carcinoma
What does chemical carcinogenesis involve?
Initiation and promotion
What do animal experiments show?
The sequence in which carcinogens are administrated is critical
What is important about the sequence in which carcinogens are administrated?
Some chemical carcinogens, called initiators, must be given first, followed by a second class of carcinogens, called promoters
What does the Ames test show?
Initiators are mutagens, while promoters cause prolonged proliferation in target tissues
What does promoter induced proliferation in target tissues culminate in?
Monoclonal expansion of mutant cells
How does a mutant monoclonal collection of cells eventually become fully malignant?
Through a process called progression
How can mutagenic chemical carcinogens be classified?
Polycyclic aromatic hydrocarbons Aromatic amines N-nitroso compounds Alkylating agents Diverse natural products
Give an example of a natural initiator
Aflatoxin
What is true of some of the mutagenic chemical carcinogens?
They are pro-carcinogens
What are pro-carcinogens?
They are only converted to carcinogens by P450 enzymes in the liver
What are carcinogens that act as both initiators and promoters called?
Complete carcinogens
What is radiation?
Any type of energy travelling through space
Is radiation mutagenic?
Some forms are
How far can ultraviolet (UV) light penetrate?
No deeper than the skin
What does ionising radiation do?
Strips electrons from atoms
What can produce ionising radiation?
X-rays
Nuclear radiation arising from radioactive elements
What does nuclear radiation comprise of?
Alpha particles, beta particles, and gamma rays
How can radiation cause damage?
It can damage DNA directly, or cause indirect damage by generating free radicals
What is the most important type of radiation?
UV
Why is UV radiation the most important type of radiation?
Because we are exposed daily from sunlight, leading to an increased skin cancer risk
What is the main exposure to ionising radiation for most people?
Natural background radiation from radon, which seeps from the earths crust
What does ionising radiation do in the body?
Damages DNA bases and causes single and double strand DNA breaks
How can infections act to cause cancer?
Some directly affect genes that control cell growth
Others do so indirectly by causing chronic tissue injury, where the resulting regenerating acts either as a promoter for any pre-existing mutations, or elses causes new mutations from DNA replication errors
What is Human Papilloma Virus (HPV) strongly linked to?
Cervical carcinoma
What kind of carcinogen is the HPV virus?
Direct
How does HPV act as a carcinogen?
It expresses the E6 and E7 proteins that inhibit p53 and pRB protein function respectively, both of which are important in cell proliferation
What kind of carcinogens are Hep B and C viruses?
Indirect
How do Hep B and C act as carcinogens?
They cause chronic liver cell injury and regeneration
Can bacteria and parasites lead to neoplasms?
Yes, indirectly
Give an example of a bacteria that can cause neoplasms?
Helicobacter pylori
How does helicobacter pylori cause neoplasms?
It can cause chronic gastric inflammation, increasing the risk of gastric carcinomas
Give an example of a parasitic cause of neoplasms
Parasitic flukes
How do parasitic flukes cause neoplasms?
They cause inflammation to the bile ducts and bladder mucosa, increasing the risk for cholangio- and bladder carcinomas respectively
How does Human Immunodeficiency Virus (HIV) increase the risk of neoplasms?
It acts indirectly by lowering immunity, and allowing other potentially carcinogenic infections to occur
What pattern of inheritance is seen with retinoblastoma?
Dominant
Does retinoblastoma occur sporadically, or just in families?
Yes
How was the differences between tumours occurring in families and those occurring in the general population explained?
Knudson postulated a ‘two hit hypothesis’
What is the two hit hypothesis?
For familial cancers, the first hit was delivered through the germline, and affected all the cells in the body. The second hit was a somatic mutation.
In the case of retinoblastoma, this was in one of the 10million+ retinal cells already carrying the first hit
In contrast, sporadic retinoblastoma has no germline mutation, and so requires both hits to be somatic mutations and to occur in the same cell.
When do initiation and promotion lead to neoplasms?
When they affect proto-oncogenes and tumour suppressor genes
What are tumour suppressor genes?
Genes that inhibit neoplastic growth
Why do tumour suppressor genes need two hits?
Because both alleles must be inactivated
What are oncogenes?
Genes that enhance neoplastic growth that are abnormally activated versions of normal genes called proto-oncogenes
Do proto-oncogenes need two hits to convert them to oncogenes?
No, only one allele of each proto-oncogene needs to activated to favour neoplastic growth
What was the first human oncogene to be discovered?
RAS
In what proportion of malignant neoplasms is RAS mutated in?
Approx 1/3
What does the RAS proto-oncogene encode?
A small G protein that relays the signals into the cell that eventually pushes the cell past the cell cycle restriction point
What does mutant RAS do?
Encodes a protein thats always active, ultimately producing a constant signal to pass through the cell cycle’s restriction point
What does the RB gene do?
Restrains cell proliferation by inhibiting passage through the restriction point
What does inactivation of both RB alleles allow?
Unrestrained passage through the restriction point
What does the action of RB and RAS show?
How one component of growth control, the restriction point, can be deregulated either by an activated oncogene or inactivated TS gene
What can proto-oncogenes encode for?
Growth factors Growth factor receptors Plasma membrane signal transducers Intracellular kinases Transcription factors Cell cycle regulators Apoptosis regulators
Give an example of a growth factor
PDGF
Give an example of a growth factor receptor
HER2
Give an example of a plasma membrane signal transducer
RAS
Give an example of an intracellular kinase
BRAF
Give an example of a transcription factor
MYC
Give an example of a cell cycle regulator
CYCLIN D1
Give an example of an apoptosis regulator
BCL2
What do tumour suppressor genes encode for?
Proteins in the same pathways, but with anti-growth effects
Give an example of a tumour suppressor gene?
TP53
What do some inherited cancer syndromes have?
Germline mutations that cause malignant neoplasms indirectly by affecting DNA repair
What inheritance pattern does xeroderma pigmentosum (XP) show?
Autosomal recessive
What is XP due to?
Mutations in one of the 7 genes that affect DNA nucleotide excision repair (NER)
What are patients with XP sensitive to?
UV damage
What is the result of patients with XP being sensitive to UV damage?
They develop skin cancer at a young age
What inheritance pattern does hereditary non-polyposis colon cancer (HNPCC) show?
Autosomal dominant
What is HNPCC syndrome associated with?
Colon carcinoma
What happens in HNPCC syndrome?
The germline mutation affects one of several DNA mismatch repair genes
What is familial breast carcinoma associated with?
Either BRCA1 and BRCA2 genes, which are important for repairing double strand DNA breaks
Can the mutations found in hereditary cancers be found in sporadic malignant neoplasms?
Yes
What stage of mitosis can be abnormal in malignant cells?
Chromosomal segregation during mitosis
What do the alterations found in hereditary neoplasms account for?
The accelerated mutation rate found in the malignant neoplasms that is known as genetic instability
What do genes that maintain genetic stability belong to?
A class of tumour suppressor genes called caretaker genes
What do most malignant tumours require?
Alterations affecting a combination of multiple TS genes and proto-oncogenes
What is the need for most malignant tumours to have alterations affecting a combination of TS genes and proto-oncogenes illustrated by?
Colon carcinoma
What does colon carcinoma usually start as?
A colonic adenoma, from which arises a carcinoma
What is the the conversion of adenoma to carcinoma known as?
The adenoma-carcinoma sequence
What is shown to happen during the adenoma-carcinoma sequence?
Mutations accumulate
How has it been shown that mutations accumulate during the adenoma-carcinoma sequence?
Analysis of early adenomas, later adenomas, primary carcinomas and metastatic carcinomas
What is the time frame for the adenoma-carcinoma sequence?
Typically decades
What does the adenoma-carcinoma sequence illustrate?
A general principle of step-wise accumulation of mutations in malignant neoplasms
What is the steady accumulation of multiple mutations called?
Cancer progression
How does cancer evolve?
By initiation and promotion, and then finally by progression
What is the exact number of mutations required for a fully evolved malignant neoplasm?
Unknown, but thought to be approx. 10 or less
What is it now believed that a fully evolved malignant neoplasm exhibits?
6 hallmarks of cancer, plus one enabling feature
What are the six hallmarks of cancer?
Self-sufficiency in growth signals
Resistance to growth stop signals
No limit on the number of times a cell can divide (cell immortilisation)
Sustained ability to induce new blood vessels (angiogenesis)
Resistance to apoptosis
The ability to invade and produce metastases
What kind of neoplasms are the hallmarks related to?
Hallmarks 1 to 5 are primarily about increased growth, and therefore likely to be relevant to both benign and malignant neoplasms
Hallmark 6 is exclusively relevant to malignant neoplasms
What is genetic instability regarded as?
An enabling characteristic
What is the model of cancer pathogenesis?
First, somatic cells are exposed to environmental carcinogens that are either initiators or promoters, culminating in a monoclonal population of mutant cells
By chance, some of these clones harbour mutations affecting a proto-oncogene or tumour suppressor gene, which protein transcripts play crucial roles in cell signalling pathways affecting ‘hallmark’ changes.
During progression the cells acquire further activated oncogenes, or inactivated tumour suppressor genes, including the ones that cause genetic instability
This eventually results, after many years or even decades, in a population of cells that has acquired a set of mutations that produce all of the ‘hallmarks of cancer’
What % of cancers have inherited mutations in the germline present?
5%
