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1

What do you mean when you say the cause of Neoplasia is multi-factorial?

Due to a combination of intrinsic (age/gender etc.) and extrinsic factors (related to environment and behaviour)

2

What are the 5 leading dietary and behavioural risks that leads to more than 30% of cancer deaths?

- High BMI
- Low fruit and vegetable intake
- Lack of physical activity
- Alcohol use
- Tobacco use (Associated with 1/4 of all cancer deaths)

3

2-napthylamine is an industrial carcinogen used in the dye manufacturing industry.

What are 3 things we learnt from malignant neoplasms caused by this chemical?

- There is a long delayed between carcinogen exposure and onset of malignant neoplasm

- Risk of cancer depends on total carcinogen dosage

- There is sometimes organ specificity for certain carcinogens
(2-napthylamine caused bladder carcinoma)

4

What are the 5 classes of chemical carcinogens (some are pro-carcinogens)

- Polycyclic aromatic hydrocarbons
- Aromatic amines
- N-nitroso compounds
- Alkylating agents
- Diverse natural products

5

Name 2 Carcinogens that can be classed as Diverse Natural Products

- Asbestos (Normally not harmful but releases damaging substance when broken down)

- Aflatoxin (Made by Aspergillus, is a risk factor for liver cancer)

6

How and where are Pro-carcinogens converted to Carcinogens?

What do you call carcinogens that act as both initiators and promotors?

By Cytochrome P450 enzymes in liver

Complete carcinogens

7

Nuclear radiation comprises Alpha, Beta particles and Gamma rays

Does UV light penetrate deeper than skin?

In what 2 ways can radiation damage us?

No

Direct damage to DNA
Indirect damage by generating free radicals

8

What is the most important type of radiation?

What is the main exposure to ionising radiation for most people?

UV (we are exposed daily from sunlight-> Increased risk of skin cancer)

- Natural background radiation from Radon, which seeps from Earth’s crust
- (Medical tests can also be significant)

9

Ionising radiation removed electrons from atoms and includes X-rays and nuclear radiation from radioactive elements.

How does it damage DNA directly in 2 ways?

- Damages DNA bases
- Cause single and double strand breaks

10

Some infections are carcinogenic, and can act Directly or Indirectly.

How?

Directly: Affect genes that control cell growth

Indirectly: Cause chronic tissue injury, where resulting regeneration acts as a Promotor for pre-existing mutations OR causes new mutations from DNA replication errors

11

Name 1 virus that has direct carcinogenic effects
Name 1 virus that has indirect carcinogenic effects

Direct: HPV
Indirect: Hep B/ C

(HIV causes reduced immunity so more susceptible to cancer)

12

HPV is strongly linked to cervical carcinoma

Explain its direct effects as a carcinogen

Expresses E6 and E7 proteins

E6 inhibits p53 function (Preventing apoptosis)
E7 inhibits pRB function (Retinoblastoma protein)

(Both are important in cell proliferation)

13

How do Hep B and C have indirect effects as a carcinogen?

Cause chronic hepatocyte injury and regeneration

14

How does Helicobacter pylori act as a carcinogen indirectly?

Which cancer does it increase the risk of?

Caused chronic gastric inflammation

Increases the risk of Gastric Carcinoma

15

How do Parasitic flukes act as a carcinogens indirectly?

Which cancers do they increase the risk of?

Cause inflammation in Bile Ducts and Bladder Mucosa

Increased risk of Cholangiocarcinoma and Bladder Carcinoma

16

What is the 2 hit hypothesis in Familial and Sporadic cancers?

(Retinoblastoma can be Familial or Sporadic)

Familial;
- First hit is a mutation to the germ line cells so all cells in body affected
- Second hit is a somatic mutation

Sporadic;
- No germline mutation
- Both hits are somatic mutations and are in the same cell

17

The 1st human oncogene to be discovered was RAS. In what proportion of malignant neoplasms is this gene mutated?

A third

18

The normal RAS proto-oncogene encodes a protein that releases signals into the cell that eventually pushes the cell past the restriction point.

What does Mutant RAS do?
What does the RB gene do, in contrast?

Encodes a protein that is always active, so there is a constant signal to pass though the restriction point.

RB gene restrains cell proliferation by inhibiting passage through the restriction point (Regulates the restriction point)

(Thus restriction point can be deregulated by either an activated oncogene or inactivated TS gene)

19

What are 7 things that prot-oncogenes can encode?

- Growth factors (PGDF)
- Growth factor receptors (HER2)
- Plasma membrane signal transducers (RAS)
- Intracellular kinases (BRAF)
- Transcription factors (MYC)
- Cell cycle regulators ( Cyclin D1)
- Apoptosis regulators (BCL2)

20

Xeroderma Pigmentosum is Autosomal Recessive. What is the pathology of this cancer?

What are these patients sensitive to?
What is the result of this?

Due to mutations in one of the 7 genes that affect DNA Nucleotide Excision Repair.

Very sensitive to UV damage, so develop skin cancer at a young age

21

Herditary Non-Polyposis Colon Cancer Syndrome (HNPCC Syndrome)

1. What is the inheritance pattern?
2. What cancer is it associated with?
3. Describe the pathology

1. Autosomal Dominant
2. Colon carcinoma
3. Mutation affects one of the DNA mismatch repair genes

22

Describe the pathology of Familial Breast Carcinoma

Mutations in BRCA1/ BRCA2 genes, which are involved in repairing double strand DNA breaks

(They can also be found in Sporadic Malignant Neoplams)

23

What is Genetic Instability?

Alterations in chromosome segregation during mitosis, which account for the accelerated mutation rate found in malignant neoplasms.

24

What are caretaker genes? (A class of tumour suppressor genes)

Genes that maintain genetic stability

25

What is the Adenoma-Carcinoma sequence?

A stepwise pattern of mutational oncogene activation and tumour suppressor gene inactivation

26

The exact number of mutations needed for a fully evolved malignant neoplasm is unknown.

How many is it thought to be approximately?

10 or less

27

A fully evolved malignant neoplasm exhibits 6 hallmarks of cancer AND 1 enabling feature

What are the 6 hallmarks of cancer?

1. Self sufficiency in growth signals
2. Resistance to growth stop signals
3. Cell Immortalisation (No limit on number of how many times a cell can divide)
4. Sustained ability to induce new blood vessels (Angiogenesis)
5. Resistance to apoptosis
6. Ability to invade and produce metastases

(Hallmark 6 is exclusively relevant to malignant neoplasms)

28

A fully evolved malignant neoplasm exhibits 6 hallmarks of cancer AND 1 enabling feature

What is 1 Enabling feature

Genetic instability