Session 9 Flashcards by Aleem Hussain

What is carcinogenesis?

Causes of cancer

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Name three intrinsic host factors that account for cancer risk

Hereditary
Age
Gender

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Extrinsic factories related to… (2)

… account for cancer risk

Environment

Behaviour

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Much of the increased cancer incidence over the last century is due to…

Prolonged life span

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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

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Most of the evidence about cancer risk comes from…

Epidemiological and animal studies

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Do intrinsic or extrinsic factors account for the majority of a population’s cancer risk?

Extrinsic - ~85%

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Extrinsic carcinogens fall into which 3 main categories?

Radiation
Infection
Chemicals

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Give an example of an industrial carcinogen used in the dye manufacturing industry

2-napthylamine

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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

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2-napthylamine has particular organ specificity. What cancer does it cause?

Bladder carcinoma

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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)

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Is the sequence in which carcinogens are administered critical?

Yes - chemical carcinogens called INITIATORS must be given first followed by carcinogens that are PROMOTERS

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The Ames test showed that initiators are…

The Ames test showed that promoters cause…

Mutagens

Cause prolonged cell proliferation in tissues

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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

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Some chemical carcinogens are ‘pro-carcinogens’ and converted to carcinogens by…

Cytochrome P450 in the liver

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What are complete carcinogens?

Carcinogens that act as both promoters and initiators

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Give an example of a complete carcinogen

Cigarette smoke

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What two main types of radiation can be mutagenic?

UV Radiation

Ionising radiation

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Ionising radiation includes… (2)

X rays

Nuclear radiation

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Nuclear radiation comprises… (3)

Alpha particles
Beta particles
Gamma rays

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Ultraviolet light does not penetrate deeper than…

Skin

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How can radiation damage DNA?

Directly

Indirectly through the production of free radicals

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We are exposed daily to sunlight exposing us to more ____ radiation

This leads to an increased risk in which cancer?

Skin cancer

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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