MoD S11 - Neoplasm III Flashcards Preview

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Flashcards in MoD S11 - Neoplasm III Deck (30):

What are the two major categories of factors for development of cancer?

Gives some examples of the types of factors encompassed by these categories

- Hereditary
- Age
- Gender

- Environment
- Behaviour


What are the 5 leading behavioural and dietary risks for cancer development?

What percentage of overall cancer deaths can these factors account for?

High BMI
Low fruit and vegetable intake
Lack of physical activity
Tobacco use
Alcohol use



What proportion of cancer deaths are attributable to smoking tobacco?

What is the proportion of cancer that is attributable to all extrinsic risk factors?




What are the 3 main categories of extrinsic carcinogens?



Give 2 occupations associated with development of tumours and give the carcinogenic agent in each case

Office worker:
- Asbestos
- Lung cancer, malignant mesothelioma

Dye manufacturing:
- 2-napthylamine


Give an example of how an extrinsic carcinogen may demonstrate some of the behaviours of carcinogenesis

2-napthylamine exposure (industrial, dye manufacturing)

Shows that:
- Carcinogenesis is dose dependent
- There can be a long delay between exposure and malignant neoplasm formation
- The can be organ specificity (Bladder carcinoma for 2-nap)


Give the 3 stages of carcinogenesis and give a short description of each

- Exposure to mutagen/carcinogen

- Exposure to substance that enhance proliferation

- Expansion of a monoclonal population of malignant cells


Give a description of initiatiors

Carcinogenic agent (E.g. PAH, Radiation)

Exposure to sufficient dose causes mutation (permanent DNA damage)

Effect modified by DNA repair and genetic factors

Initiation alone not sufficient for tumour formation


Give a description of promoters:

Can be hormones, local tissue reponses, immune responses

Can induce tumours only in 'intiated cells'

Not enough on their own for tumourgenesis

Cellular changes are reversible (remove promoter and cell return to normal)

Enhances proliferation to increase incidence of mutation


List the types of initiator and give mechanisms of action where applicable

Some of these carcinogens are not carcinogenic before introduction into the body, explain

Polycyclic aromatic hydrocarbons:
- Hydroxylated by the body to active form

Aromatic amines:
- Hydroxylated and conjugated by liver (glucoronic acid)
- Deconjugated in urinary tract to active form that sits in bladder

Alkylating agents:
- Bind directly to DNA

- N-nitroso compounds
- Diverse natural products (E.g. Aflatoxin)

Some of these are proto-carcinogens that must be metabolised by CYP450 enzymes before becoming carcinogenic


What substances act as both initiators and promoters?

Complete carcinogens


Give examples of mutagenic radiation

Why are these forms of radiation mutagenic?

Ionising radiation:
- Mutagenic as it strips electrons from atoms
- Damage DNA directly
- Damage DNA via free radical production (Also UV light)
- Damage overwhelms repair mechanisms to cause mutation

- X rays
- Gamma rays
- Nuclear radiation (A, B, G)

UV light :
- Also mutagenic
- Damage DNA via free radical production
- Damage overwhelms DNA repair mechanisms to cause mutation



What are our most significant sources of mutagenic radioactive exposure?

Sunlight (UV waves)

Radon gas (Ionising radiation)


How is infection involved in carcinogenesis?

Hint: 2 types of mechanism

Some infections directly affect genes that control cell growth

Others are indirectly carcinogenic by causing chronic inflammation:
- Regeneration acts as promotor for previous initiator mutation
- New mutations due to cell replication errors


Give 3 examples of carcinogenic viral infection

Give specific mechanisms

Hepatitis B:
- Associated with hepatocellular carcinoma
- Viral DNA integrated into host genome
- Causes liver cell injury/regenerative hyperplasia
- Increase in cell division gives increased risk of mutation

Epstein Barr:
- Associated with Burkitt's lymphoma, some hodgkin's lymphoma
- Infects epithelial cells or oropharynx and B cells
- Viral genes dysregulate normal proliferative and survival signals
- Acquisition of mutation potentiated

Human papilloma virus:
- Genes disrupt normal cell cycle
- Genes incorporated into host genome, driving proliferation


Give an example of bacterial infection carcinogenesis

Helicobacter pylori:
- Indirect mechanism
- Causes chronic gastric inflammation


What is the two hit hypothesis?

Explains the difference in tumours with seemingly familial versus general population cancers

The first hit is delivered through germline mutation in families then mutation of caused by other factors constituted the second hit, this leads to malignant neoplasm development

In general population tumours the first and second hits must both be acquired mutations, again leading to development of malignant neoplasms

Hence those with germline mutations that are pre-cancerous are more likely to develop malignant neoplasm as they only require one 'hit' of mutation versus two


What type of genes does the two hit hypothesis refer too?

Tumour suppressor genes


Define Tumour suppressor gene

Define proto-oncogene

- A gene that encodes a protein that suppresses growth and therefore cancer

- A normal gene that can become an oncogene (tumour promoting gene) upon mutation or increased expression


Describe proto-oncogenes

Present in all normal cells

Involved in normal growth and differentiation, DNA sequence identical to viral oncogenes

Can be modified to become oncogenes (mutation, amplification, translocation) making their products oncoproteins

This allows the cell to escape normal growth control, becoming self sufficient (no need for external growth signals)

Only one allele needs to be mutated for each gene to cause neoplasia


Describe the RAS gene


Proto-RAS encodes for a small G-protein that relays signals from the cell membrane to push the cell past the restriction point in the cell cycle (End of G1)

RAS mutation forms and 'always active' version of ras that pushes the cell past the restriction point regardless of mutations that would normally trigger apoptosis

Mutated RAS found in 1/3 of all malignant neoplasms


Describe the C-myc and HER-2 genes

- Binds to DNA, stimulating synthesis
- Amplified in neuroblastoma, breast cancer
- Translocation 8 to 14 in Burkitt's lymphoma

- Encodes for growth factor receptor
- Amplified in 25% of breast cancer
- Herceptin is competitive antagonist


Give two examples of tumour suppression genes

Retinoblastoma gene (RB):
- Passage through restriction point governed by phosphorylation of pRB
- Inactivation of both RB alleles allows unrestricted passage of a cell through the restriction point

- Guardian of genome
- Approx 50% of tumours contain mutated p53
- Gene encodes for nuclear protein that binds to and modulates expression of genes important for cell cycle arrest, DNA repair and apoptosis


Give 3 examples of inheritance of oncogenes and the disease they're associated with

Familial adenomatous polyposis:

Breast cancer:
- BRCA 1/2

Li Fraumeni syndrome:
- p53


How can germline mutations affect DNA repair?

Give examples

Germline mutations can cause malignant neoplasm indirectly by affecting DNA repair

Xerodermapigmentosum (XP):
- Germline mutation to one of the 7 genes that control nucleotide excision repair
- These patients are very sensitive to UV light damage and develop skin cancers early in life

Ataxia Telangiectasia:
- Double strand break repair not possible
- Sufferers die before age 25, commonly of cancer

Hereditary non-polyposis colon cancer (HNPCC):
- Germline mutation affects one of the mismatch repair genes

Familial breast cancer:
- BRCA1 or BRCA2 genes mutated
- Repair of double strand breaks compromised


What is the end result of mutations to DNA repair genes? (in general)

What factors resist the effects of these mutations?

Increased rate of mutation leading to malignant neoplasm

In malignant neoplasms, the accelerated mutation rate is known as genetic instability

Genes that maintain genetic stability belong to a class of tumour suppressor genes known as 'caretaker genes'


What is the adenoma-carcinoma sequence?

What does this process demonstrate?

Analysis of early adenoma, later adenoma, primary carcinoma and metastatic carcinoma shows that mutations accumulate over a long time frame (often decades)

Demonstrates how steady accumulation of mutation required for malignancy (known as cancer progression)

Multiple tumour suppressor and proto-oncogene mutations are necessary for progression to continue

Thought to be 10 or less mutations necessary for malignancy


What are the 6 hallmarks of cancer?

How do these relate to benign vs malignant neoplasm?

1. Self-sufficiency in growth signals
2. Resistance to growth stop signals
3. Cell immortalisation (infinite divisions possible)
4. Sustained ability to promote angiogenesis
5. Resistance to apoptosis
6. Ability to invade and produce metastases

1 - 5 likely to apply to both benign and malignant

6 exclusively malignant


In brief, run through the progression of somatic cell to malignant neoplasm

Somatic cell exposed to environmental carcinogens (5% of cancers have germline mutations as well)

These are initiators, promoters or complete carcinogens

This culminates in a population of monoclonal mutant cells

Some of these clones harbour mutation affecting tumour suppression or proto-oncogenes whose protein plays a crucial role in cell signalling pathways relating to the hallmarks of cancer

During progression the cell acquires further mutated tumour suppressor and oncogenes which causes genetic instability

This will result (after years or decades) in a population of malignant cells with all the hallmarks of cancer


Describe 3 conditions that pre-dispose tumours and the cancer types that commonly arise

Ulcerative colitis:
- Colorectal carcinoma
- DNA damage and micro-satellite instability

- Present in 85 - 90% of hepatocellular carcinoma
- Some association due to chronic viral hepatitis

Adenoma of colon/rectum:
- Adenocarcinoma