L20 - Mechanisms of Oncogenesis

Question 1

What is cancer?

Answer 1

A group of diseases characterised by abnormal cell proliferation, tumour formation, innvasion of neighbouring normal tissue and metastasis to form new tumours at distant sites.

Question 2

What are carcinomas?

Answer 2

cancers that occur in epithelial cells

Question 3

What are sarcomas?

Answer 3

cancers that occur in mesoderm cells like bone and muscle

Question 4

What are adenocarcinomas?

Answer 4

cancers that are found in the glandular tissue

Question 5

What is meant by a germline mutation?

Answer 5

a germline mutation is when there is a damage/change in the DNA of egg or sperm cells, perhaps due to point mutations or deletions. This mutation is inheritable and can be passed onto offspring. It rarely causes cancer immediatly however that person is at increased risk of developing cancer.

Question 6

What is meant by somatic mutations?

Answer 6

Arises from a normal cell of the body, and cannot be passed onto offspring. It is however, passd onto the daughter cells each time the cell replicates. All cells of the tumour arise from one cell - developmental process of tumour is clonal

Question 7

What are oncogenes?

Answer 7

Normal genes within cells that regulate growth. If an oncogene acquires a mutation in one of the alleles, it leads to signals that cause uncontrolled growth

Question 8

What are tumour supressor genes?

Answer 8

They inhibit growth and tumour formation. They act as braking signals during phase G1 of the cell cycle to stop/slow cells before S phase.
There must be 2 individual mutations in the tumour supressor genes for them to malfunction. If they are mutated, the normal brake mechanism will be disabled, resulting in uncontrolled growth.

Question 9

Describe Model 1 (chemical carcinogens) as a model of carcinogenesis?

Answer 9

MODEL 1 - CHEMICAL CARCINOGENS

Carcinogens affect any point of the muti-step process that is cancer, including the initiation, promotion and progression stages.

They work by altering the structure of DNA, and if this damage isn’t repaired, there will be an accumulation of damage

In the majority of instances, chemical caricnogens can induce this DNA damage and act in a genotoxic manner.

Four of the major groups: polycyclic aromatic hydrocarbons, aromatic amines, nitrosamines and alkylating agents exert their effects by adding functional groups to DNA bases called DNA adducts.

Question 10

What are some examples of chemical carcinogens?

Answer 10

polyclyclic aromatic hydrocarbons

aromatic amines

azo dyes

nitrosamines

carbamates

halogenated compounds

alkylating agents

Question 11

What are some examples of physical carcinogens?

Answer 11

Radiation (ionising or UV radiation)

Asbestos

Question 12

What are some examples of heritable carcinogens?

Answer 12

genetic predisposition

Question 13

What are some examples of viral carcinogens?

Answer 13

Hepatitis B

Epstein Barr

Question 14

Describe Model 1 (physical carcinogens) as a model of carcinogenesis?

Answer 14

MODEL 1 - PHYSICAL CARCINOGENS

They act by imparting energy into the biological material and altering the bonding of molecules.

Ration is the primary physical agent. UV radiation does not penetrate further that the skin.

Radiation causes pyrimidine dimers and DNA breaks, which can be repaired. However if repair mechanims are mutated, it leads to worse damage like translocations and mutations.

Question 15

What test can be used to test whether a chemical is a carcinogen?

Answer 15

The Ames test:
it is a test used to determine the mutagenic activity of chemicals by observing whether they cause mutations in sample bacteria.

Question 16

Describe Model 1 (heritable carcinogens) as a model of carcinogenesis?

Answer 16

MODEL 1 - HERITABLE CARCIOGENS

Due to inherited germline mutations which increase the risk of developing cancer.

In most hereditary malignant syndromes, the elevated cancer risk is due to a mutation of a single gene ( these are monogenic hereditary diseases)

The affected genes usually have a controlling function on the cell cycle or DNA repair

Question 17

Describe Ataxia Telangiectasia as a DNA repair defect disease?

Answer 17

neuromoto dysfunction, dilation of blood vessels and spider viens in the eyes.

Mutation in the ATM gene which codes for serine/threonine kinase that is recruited and activated by dsDNA breaks leading to to cell cycle arrest, DNA repair and apoptosis.

can lead to lymphoma, leukeamia and breast cancer

Question 18

Describe Bloom’s syndrome as a DNA repair defect disease?

Answer 18

short statute, skin rash after exposure to the sun

Mutation in the BLM gene that provides instructions for coding a memeber of the RecQ helicase family that helps manitain the integrity and structure of DNA

leads to skin cancer, basal cell carcinoma, and squamous cell carcinoma

Question 19

Describe Lynch type as a DNA repair defect disease?

Answer 19

LS dosent cuase any symptoms, the first sign that a person has it, is when symotoms of bowel and womb cancer develop.

Mutations in DNA mismatch repair genes, notable MLH1, MSH2, PMS2 and MSH6.

Can lead to Colorectal cancer

Question 20

Describe Model 1 (viral carcinogens) as a model of carcinogenesis?

Answer 20

Most harm is caused when viruses multiply inside the infected cell, kill the cell and then release progeny to further infect other cells

Sometimes viruses can cause cancer, and this occurs during the later phase of infection, when there is restricted gene expression. This can incude oncogenes of the virus. It drives expression of genes that will cause transformation of the cell.

Question 21

What are the poperties of tumourigenic viruses?

Answer 21

• have stable association with cells (chromosomal integration with cellular genes)
• Must not kill cells (has to supress the lytic cycle)
• has to evade the immune system’s surveillance of infected cells (genes expressed in later stages re non-immunogenic, so they won’t be detected by the immune system)

Question 22

What are some DNA viruses that are associated with hman cancer?

Answer 22

Epstein-Barr Virus - lymphoma and nasopharyngeal cancer

Papilloma Viruses - cervical cancer and warts

Hepatitis B and C - hepatoma

Question 23

What ar some RNA viruses that are associated with human cancer?

Answer 23

HLV - 1 : adult T-cell leukeamia and lymphoma

Question 24

Describe Model 2 of Carcinogenesis?

Answer 24

genome instability and familiality.
On average 60,000 mutations can occur a day in the body, however they are usually repaired.

Knudson hypothesis:
he performed analysis on cases of the 2 types of retinoblastoma - the inherited type (familiar form) or the sporadic form. He found that patients with the sporadic form, developed the tumour much later in life than the inherited type patients.

Question 25

Describe Model 3 of Carcinogenesis?

Answer 25

Non- genotoxic effects
Several important modulators of cancer risk (diet, obesity, hormones and insulin resistance) do not seem to act through a structural change in DNA but rather a functional changes including epigenetic events.

Non toxic carconogens act as:

• tumour promoters
• endocrine modifiers
• receptor mediators
• immunosupressants
• inducers of tissue specific toxicity and inflamatory responses

Question 26

Describe Model 4 of Carcinogenesis?

Answer 26

Darwinian
Clonal expansion and cells selection.
As cells proliferate and mutations accumulate , cells do not acquire the same mutations. They are consatntly evolving and there is a natural selection of cells with growth advantage

Question 27

Describe Model 5 of Carcinogenesis?

Answer 27

Tissue Organisation

Tissue Organisation Field Theory:
carcinogenesis is primarily a problem of tissue organsiation
Carcinogenic agents destroy the normal tissue architecture thus disrupting cell-to-cell siganalling and compromising genomic integrity. As a result DNA mutations are effect of tissue level events, not the cause.

Question 28

What is Cancer Immunoediting?

Answer 28

The process by which the immune system can both constrain and promote tumour development.

Question 29

State the three E’s of Cancer Immunoediting?

Answer 29

ELIMINATION
EQUILIBRIUM
ESCAPE

Question 30

What happens in the Elimination phase of Cancer Immunoediting?

Answer 30

The immune system is able to eradicate developing tumours

Question 31

What happens in the Equilibrium phase of Cancer Immunoediting?

Answer 31

When there is incomplete removal, tumour cells remain dormant and enter equilibrium (this phase lasts many years - exposure to carcinogens may have occured decades ago, but consequnces are still imminent)

The immune system exerts a potent and relentless pressure that contains the tumour . During this phase, some of the tumour may mutate or give rise to genetic variants that survive, grow and enter the next phase

Question 32

What happens in the Escape phase of Cancer Immunoediting?

Answer 32

The expanding tumour mass/populations then becomes clinically detectable