3 - Aetiology of Carcinogenesis

Question 1

Carcinogenesis

Answer 1

The process by which normal, healthy cells transform into cancer cells

Question 2

Somatic mutation theory

Answer 2

• Cancers arise from mutations in individual cells, passed on through division
• Clinically observable cancer is result of accumulating multiple mutations

Question 3

Mutator phenotype

Answer 3

An acquired increase in rate of mutation

Question 4

What does first mutator acquisition relate to

Answer 4

• Increased cell division
• Abnormal DNA replication
• Damaged DNA repair mechanisms.

Question 5

Lethal mutation

Answer 5

Disruptive in a manner that harms or kills the cell

Question 6

Passenger mutation

Answer 6

Consequential, no selective advantage

Question 7

Driver mutations

Answer 7

Provides a selective advantage

Question 8

Multi step process of mutation

Answer 8

• Cancer causing mutations are cumulative but randomly ordered
• Mutation can occur in any cell at any time
• Most likely to occur during DNA replication
• Will only be passed on if cell divides

Question 9

Stepwise mutations

Answer 9

• Results in heterogeneity between tumours in an individual with metastatic disease or within a single tumour
• Has implications for therapy (one cell with resistance survives treatment then replicates so cancer comes back resistant)

Question 10

Examples of tumours co-opting existing cellular pathways

Answer 10

• VEGF disruption can change angiogenesis
• P53 disruption can interfere with apoptosis
• MAPK signalling can impact on tissue invasion, growth signals self-sufficiency AND proliferation

Question 11

Selective pressures of tumours

Answer 11

• Immune system
• Tumour suppressor genes
• Microenvironment (e.g. anaerobic respiration under hypoxia)

Question 12

Feedback loop of cancer

Answer 12

Less tumour cell death –> more proliferation –> more rounds of DNA replication –> more chance of passing mutations on –> more opportunity for mutation and instability

Question 13

Proto-oncogenes typically are one of

Answer 13

• Cell division stimulators
• Differentiation blockers
• Apoptosis inhibitors
• Components of signalling pathways
• Growth factors.

Question 14

How do proto-oncogenes become oncogenes

Answer 14

When expressed at increased levels, resulting from either:
- Amplification leading to more copies of the gene
- Translocation to a more active promotor
- Mutation resulting in a fusion protein with oncogene activity

Question 15

How many oncogenes currently known

Answer 15

> 40

Question 16

Examples of oncogenes

Answer 16

MYC and RAS

Question 17

MYC

Answer 17

• Transcription factor
• Overexpressed/activated in >50% of human cancers
• Coordinates many cellular processes (e.g. angiogenesis)
• Proliferative arrest
• Blocks senescence and differentiation

Question 18

MYC addiction

Answer 18

• Tumour survival often depends on high MYC
• Not sufficient alone for carcinogenesis

Question 19

RAS

Answer 19

• GTPase signalling proteins
• 3 RAS genes
• RAS on/off activity is sped up by regulatory proteins

Question 20

RAS regulatory proteins

Answer 20

• Guanine nucleotide exchange factors (GEF) catalyse exchange of GDP with GTP (RAS “switched on”).
• GTPase-activating proteins (GAP) catalyse hydrolysis of GTP to GDP (RAS “switched off”).
• Mutant RAS don’t allow GAP to coordinate hydrolysis (RAS is stuck ‘on’)

Question 21

3 RAS genes

Answer 21

• KRAS, NRAS, HRA
• RAS mutants are 85% KRAS

Question 22

RAS effects

Answer 22

• Cell survival and growth
• Transcription
• Cell cycle progression
• Cell migration

Question 23

Tumour supressor genes

Answer 23

• “anti-oncogenes”
• Problem if these are knocked out
• Often requires both alleles being knocked out
• Hereditary susceptibility
• Often have suppressive or regulatory activity

Question 24

Suppressive or regulatory activity of tumour suppressor genes

Answer 24

• Control proliferation
• Initiate apoptosis if DNA damage is detected
• Regulate adhesion i.e. stop metastasis

Question 25

Large scale mutations

Answer 25

• Less common, usually happens during mitosis
• Chromosomal gain/loss (usually lethal)
• Translocation/duplication/deletion of large fragments

Question 26

Chromosomal gain/loss

Answer 26

• Down syndrome (trisomy 21)
• Klinefelter syndrome (XXY)

Question 27

Translocation/duplication/deletion of large fragments

Answer 27

• Philadelphia chromosome seen in CML
• D deletion syndrome seen in retinoblastoma

Question 28

Philadelphia chromosome

Answer 28

Translocation between long arms of chromosomes 9 and 22

Question 29

D deletion syndrome

Answer 29

Loss of long arm of chromosome 13

Question 30

Small scale mutations

Answer 30

• Point mutations
• Proteins can still be made
• Very subtle differences
• May prevent one particular role
• Frame shift in reading frame

Question 31

Carcinogenesis causes

Answer 31

Endogenous or exogenous (mainly)

Question 32

Endogenous causes

Answer 32

• Spontaneous
• Random mistakes in DNA replication
• Chance increases with age
• Lifetime incidence of many cancers correlates with normal homeostatic cell division rates in that tissue

Question 33

Exogenous causes

Answer 33

• Carcinogens causing cancer
• Mutagens cause genetic mutation
• Most carcinogens are mutagenic

Question 34

Three main groups of carcinogens

Answer 34

• Chemical (e.g. alcohol)
• Radiological (e.g. UV, x-ray)
• Biological (e.g. viral, bacterial)

Question 35

Mechanisms of action of environmental carcinogens

Answer 35

• Sources of carcinogen vary in their likelihood of causing cancer in broader or more restricted range of tissues
• Depends on site of exposure
• Exposure to higher amounts can allow chemical carcinogens to accumulate in other organs in concentration that can cause disease

Question 36

Alcohol

Answer 36

• Increases risk of mouth, pharynx, larynx, oesophagus, bowel, liver, breast cancer
• Via blood stream, affects many tissues/organs around the body

Question 37

Alcohol mechanisms of causing cancer

Answer 37

• Ethanol -> acetaldehyde by alcohol dehydrogenase (damages DNA & stops cells from repairing)
• Ethanol may also cause direct tissue damage to cells of mouth/throat
• Acts as a solvent for other carcinogens (e.g., from smoking);
• Increases level of hormones such as oestrogen (linked to breast cancer) or insulin.

Question 38

How many annual cases of cancer in Aus are attributable to long term alcohol consumption

Answer 38

> 3,200

Question 39

UV radiation

Answer 39

• 99% of non-melanoma skin cancers and 95% of melanoma caused by UV
• Sources (sun, sunbeds, sun lamps)
• UVA penetrates into dermis (Genetic damage to cells, photo-ageing, immune-suppression)
• UVB penetrates into the epidermis (Damages cells, responsible for sunburn -> melanoma)
• If damage isn’t repaired, cell may grow in uncontrolled way

Question 40

Incidence of cancer due to radiation in Aus

Answer 40

> 13,000 new cases & >1,700 deaths annually

Question 41

HPV

Answer 41

• 14 types can cause cancer (16 & 18 cause 70% of cancer)
• Chronic infection can lead to pre-cancerous lesions
• Host genome integration leads to higher risk
• Two HPV proteins strongly associated with cervical cancer

Question 42

Risk factors of HPV

Answer 42

• HPV type
• Immune status
• Coinfection (e.g. herpes simplex, chlamydia)

Question 43

Two HPV proteins strongly associated with cervical cancer

Answer 43

E6 and E7

Question 44

E6

Answer 44

Inhibits p53 (normally induces apoptosis in response to cellular stress inc DNA damage and viral infection)

Question 45

E7

Answer 45

Inhibits Rb (normally prevents cell division by blocking transcription factors)

Question 46

Cancer mutational burden

Answer 46

• Different cancer types carry characteristically different levels of mutations
• Mutational signatures differ across cancer types
• Some represent different base substitutions evenly, whilst some are remarkably specific.