Session 9 Flashcards
What is carcinogenesis?
Causes of cancer
Name three intrinsic host factors that account for cancer risk
Hereditary
Age
Gender
Extrinsic factories related to… (2)
… account for cancer risk
Environment
Behaviour
Much of the increased cancer incidence over the last century is due to…
Prolonged life span
About 30% of cancer deaths are due to which 5 leading behavioural/dietary risks?
Tobacco use Alcohol use Low fruit/vegetable intake High BMI Lack of physical activity
Most of the evidence about cancer risk comes from…
Epidemiological and animal studies
Do intrinsic or extrinsic factors account for the majority of a population’s cancer risk?
Extrinsic - ~85%
Extrinsic carcinogens fall into which 3 main categories?
Radiation
Infection
Chemicals
Give an example of an industrial carcinogen used in the dye manufacturing industry
2-napthylamine
Malignant neoplasms caused by 2-napthylamine showed that there is… (3)
A long delay between carcinogen exposure and malignant neoplasm onset
The risk of cancer depends on total carcinogen dosage
There can be organ specificity for certain carcinogens
2-napthylamine has particular organ specificity. What cancer does it cause?
Bladder carcinoma
Industrial carcinogens (e.g. Asbestos, coal tars and vinyl chloride) have an effect primarily on the relevant workers. Tobacco smoke’s carcinogenic effect is largely limited to smokers.
What is the reason for this?
Due to the dependence on dosage (e.g. Non-smokers are not getting a sufficient dose of carcinogen from passive cigarette smoke)
Is the sequence in which carcinogens are administered critical?
Yes - chemical carcinogens called INITIATORS must be given first followed by carcinogens that are PROMOTERS
The Ames test showed that initiators are…
The Ames test showed that promoters cause…
Mutagens
Cause prolonged cell proliferation in tissues
Mutagenic chemical carcinogens (initiators) can be classified into which 5 categories?
Give an example of each
Polycyclic aromatic hydrocarbons - benzopyrene
Aromatic amines - 2-napthylamine
N-nitroso compounds - dimethylnitrosamine
Alkylating agents - vinyl chloride
Natural products - asbestos
Some chemical carcinogens are ‘pro-carcinogens’ and converted to carcinogens by…
Cytochrome P450 in the liver
What are complete carcinogens?
Carcinogens that act as both promoters and initiators
Give an example of a complete carcinogen
Cigarette smoke
What two main types of radiation can be mutagenic?
UV Radiation
Ionising radiation
Ionising radiation includes… (2)
X rays
Nuclear radiation
Nuclear radiation comprises… (3)
Alpha particles
Beta particles
Gamma rays
Ultraviolet light does not penetrate deeper than…
Skin
How can radiation damage DNA?
Directly
Indirectly through the production of free radicals
We are exposed daily to sunlight exposing us to more ____ radiation
This leads to an increased risk in which cancer?
UV
Skin cancer
How can radiation indirectly damage DNA?
Through the production of free radicals
For most people the main exposure to ionising radiation is…
Natural background radiation from radon - seeps from the Earth’s crust
How can ionising radiation directly damage DNA? (2)
Alters DNA bases
Causes single/double stranded DNA breaks
Some infections are carcinogenic and can act directly or indirectly.
How can infections directly be carcinogenic?
How can infections indirectly be carcinogenic?
Directly - affect the genes that control cell growth
Indirectly - chronic tissue injury - regeneration acts as a promoter for existing mutations/causes new mutations from DNA replication errors
Human papilloma virus is strongly linked to which cancer?
Cervical Carcinoma
Give an example of an infection that is directly carcinogenic
Infection by HPV (human papilloma virus)
How does HPV work as a direct carcinogen?
Expresses E6 and E7 protein.
E6 - inhibits p53
E7 - inhibits pRB
What is the function of p53 in cells?
Regulates apoptosis
What is the function of pRB in cells?
Allows entry of the cell into the cell cycle
The E6 protein expressed by HPV inhibits…
p53
The E7 protein expressed by HPV inhibits…
pRB protein
Give two examples of infections that act as indirect carcinogens
Hep B
Hep C
How can Hep B/Hep C act as indirect carcinogens?
Cause chronic liver cell injury and regeneration —> Mutations
Give an example of a bacteria that can act as an indirect carcinogen?
How does it work?
Helicobacter pylori
Causes chronic gastric inflammation —> Increased risk of gastric cancer
How does HIV act as a carcinogen?
Indirectly by lowering the immunity and allowing other potentially carcinogenic infections to occur
Give an example of a type of cancer that is more likely to occur due to HIV
Kaposi’s sarcoma - skin
Inherited predisposition to neoplasia can occur through…
Germline mutations
What does the two hit hypothesis of neoplasia explain? Describe it.
The differences between tumours occuring in families and those occuring in the general population. Says that a cell must acquire two ‘hits’ before becoming neoplastic - more likely in familial cases as a ‘hit’ is already provided in all cells due to germline mutations
Give an example of a tumour that follows the two hit hypothesis of neoplasia
Retinoblastoma - malignant retinal tumour
What is the inheritance pattern seen in retinoblastoma?
Dominant
Describe the two hit hypothesis that retinoblastoma follows. Compare retinoblastoma running in families to sporadic retinoblastoma
Familial retinoblastoma - first hit delivered through germline affecting all cells in the body. Second hit is a somatic mutation in any retinal cell (all carry first hit)
Sporadic retinoblastoma - no germline mutation, two somatic mutations need to occur in the same cell to become neoplastic
Invitation and promotion lead to neoplasm when they affect which genes? (2)
Proto-oncogenes
Tumour suppressor genes
What are tumour suppressor genes?
Genes that inhibit neoplastic growth
How are tumour suppressor genes inactivated?
By inactivation of both alleles - two ‘hits’
What are oncogenes?
Abnormally activated versions of proto-oncogenes - enhance neoplastic growth
How many alleles of each proto-oncogene need to be activated to favour neoplastic growth?
1 allele of each proto-oncogene
What was the first human oncogene to be discovered that is mutated in ~1/3 of malignant neoplasms?
RAS
What does the RAS proto-oncogene code for?
A small G protein that results in the cell being pushed past the cell cycle restriction point
What is the normal function of the G protein coded for by RAS?
Results in the cell being pushed past the cell cycle restriction point
What is the effect of mutant RAS?
A constant signal to push a cell through the cell cycle’s restriction point is produced
Which gene restrains cell proliferation by inhibiting passage of a cell through the restriction point?
RB gene
What is the function of the RB gene?
Restrains cell proliferation by inhibiting the passage of a cell through the restriction point
Inactivation of how many RB alleles allows unrestrained passage through the restriction point of the cell cycle?
Both (2) RB alleles
Inactivation of both RB alleles in a cells allows…
Unrestrained passage of the cell through the restriction point of the cell cycle
In summary, the restriction point can be deregulated by either…
An activated/mutant RAS gene (proto-oncogene)
Inactivated pRB gene (tumour suppressor gene)
Give an example of 7 things that proto-oncogenes can code for
TS genes code for which proteins?
Growth factors Growth factor receptors Plasma membrane signal transducers Intracellular kinases Transcription factors Cell cycle regulators Apoptosis regulators
Proteins in same pathways but with anti-growth effects
How doe genetic instability affect mutation rate?
Increases mutation rate
Xeroderma pigmentosum is due to mutations in which genes?
DNA repair genes - nucleotide excision repair (NER)
In which pattern is xeroderma pigmentosum inherited?
Autosomal recessive
Which DNA repair genes are affected by xeroderma pigmentosum?
Genes that affect DNA nucleotide excision repair
What happens to patients with xeroderma pigmentosum?
They are very sensitive to UV light and develop skin cancer at a young age
What does HNPCC stand for? In which pattern is it inherited?
Hereditary non-polypsis colon cancer syndrome
Autosomal dominant
HNPCC is associated with which cancer?
Colon carcinoma
The mutation seen in HNPCC affect which DNA repair genes?
DNA mismatch repair genes
Familial breast carcinoma is associated with which two genes?
BRCA1
BRCA2
What is the function of BRCA1/BRCA2?
They are important in repairing double stranded DNA breaks
What mechanism AND genes of DNA repair are affected in…
I) xeroderma pigmentosum
II) HNPCC
III) familial breast cancer
XP - genes coding for nucleotide excision repair
HNPCC - DNA mismatch repair genes
Familial Breast Cancer - BRCA1/BRCA2 - double stranded break repair
How is chromosome segregation in mitosis affected in malignant cells?
Can be abnormal
The alterations that account for the accelerated mutation rate found in malignant neoplasms is known as…
Genetic instability
What are caretaker genes?
Genes that maintain genetic stability (a class of tumour suppressor genes)
Generally, is a single mutation in proto-oncogenes/tumour suppressor genes sufficient in making a malignant neoplasms?
No - alterations in a combination of multiple TS genes/proto-oncogenes is required
What is cancer progression?
The steady accumulation of multiple mutations in malignant neoplasms
What does colon carcinoma usually start as?
Colonic adenoma
What is the adenoma-carcinoma sequence?
Refers to the accumulation of mutations in different TS genes/proto-oncogenes resulting in what started as a adenoma progressing to a carcinoma
Give an example of a type of cancer that follows the adenoma-carcinoma sequence
Colon cancer
Colonic adenoma —> Colon carcinoma
What is the typical timeframe for the accumulation of mutations seen in an adenoma-carcinoma sequence, from early adenoma to metastatic carcinoma?
Typically decades
Cancer evolves by ___________ and _____________ and finally by _____________
Initiation
Promotion
Progression
The exact number of mutations needed for a fully evolved malignant neoplasm is unknown but is thought to be approximately…
Ten or less
It is believed that a fully evolved malignant neoplasms exhibits _____ hallmarks of cancer and ___ enabling feature
Six
One
A malignant neoplasm exhibits which 6 hallmarks of cancer?
Self-sufficiency in growth signals
Resistance to growth stop signals
No limit on the number of times a cell can divide
Sustained ability to induce new blood vessels (angiogenesis)
Resistance to apoptosis
Ability to invade/produce metastases
What is seen as the enabling characteristic of a malignant neoplasm?
Genetic instability
Give an example of a molecular alteration in neoplasms related to self-sufficiency in growth signals
HER2 gene amplification in breast cancer
Give an example of a molecular alteration in neoplasms related to resistance to anti-growth signals
CDKN2A gene deletion in melanoma
Give an example of a molecular alteration in neoplasms related to indefinite growth/divisions
Telomerase gene activation in most cancers
Give an example of a molecular alteration in neoplasms related to increased angiogenesis
VEGF expression in many cancers
Give an example of a molecular alteration in neoplasms related to resistance to apoptosis
BCL2 gene translocation in lymphoma
Give an example of a molecular alteration in neoplasms related to the ability of cancer cells to invade and produce metastases
E-cadherin mutation in gastric cancer
Initiators cause…
Promoters cause…
Mutation
Prolonged cell proliferation
Environmental carcinogens can be… (3)
Chemicals
Infections
Radiation
Genetic instability refers to…
A high frequency of mutations in the genome of a cell
