Lecture 5: Causes of cancer: Genes Vs Environment

Question 1

What are the three sources of mutations that may lead to cancer development?

Answer 1

1. Sporadic mutation resulting from damage to DNA through replicative mutations (normal errors in DNA replication causes lesions that may go unrepaired leading to mutations)
2. Sporadic mutation resulting from damage to DNA through environmental factors (E.g. ionising radiation, tobacco smoke –> carcinogens - extrinsic causes of mutations)
3. Inherited susceptibility via germline mutation (all cells in offspring contain the mutation

Question 2

What percentage of cancers are caused by sporadic mutations?

Answer 2

90%
(around 10% of cancers are caused by inherited mutations)

Question 3

True or false: sporadic mutations are largely related to the aging process?

Answer 3

True - as we get older, we are more likely to acquire a mutation that leads to cancer development.

Question 4

What is the basis of cancer predisposition syndromes?

Answer 4

Inherited germline mutations

Question 5

How are genes for cancer predisposition syndromes usually identified?

Answer 5

Linkage analysis and positional cloning
- Linkage analysis to identify the regions of the genome that are likely to contain the gene of interest
- Positional cloning to pinpoint the precise loci of genes implemented in the diease

Question 6

True or false: cancer predisposition syndromes typically show autosomal dominant inheritance and involve mutation within an oncogene?

Answer 6

False:
cancer predisposition syndromes do typically show autosomal dominant inheritance but involve mutation within a tumour suppressor gene

Question 7

What cancers can develop in individuals with an inherited mutation within the BRCA1/2 gene?

Answer 7

Tend to develop bilateral cancer in organs that come in pairs.

Question 8

What is the penetrance of mutations in cancer predisposition syndromes?

Answer 8

Highly penetrant (some up to 100%)

Question 9

Give an example of an autosomal dominant hereditary cancer syndrome (give the gene involved, risk of developing cancer, and some of the affected tissue/organs)?

Answer 9

Li Fraumeni Syndrome (LFS)
- gene: TP53 (master regulator)
- high risk of developing cancer
- develop cancer in breast, brain, leukaemia, bone and soft tissues (sarcoma)

Question 10

Give an example of an autosomal recessive hereditary cancer syndrome (give the gene involved, risk of developing cancer, and some of the affected tissue/organs)?

Answer 10

Xeroderma Pigmentosum
- gene: XPA-G or XP-V (involved in DNA repair mechanisms for UV damage)
- high risk of developing cancer
- develop cancers in skin

Question 11

What are the two main types of skin cancer and what are their cells of origin?

Answer 11

1. Non-melanoma skin cancers such as basal cell carcinoma and squamous cell carcinoma - these cancers originate from keratinocytes and are rarely life-threatening and more common
2. Melanoma skin cancer originates from melanocytes and are often fatal but less common

Question 12

Why are melanomas more often fatal than non-melanoma cancers?

Answer 12

The melanocytes are closer to the vasculature of the skin than the keratinocytes so have greater capability of metastasis

Question 13

What is familial atypical multiple mole melanoma syndrome (FAMMM)?

Answer 13

An inherited condition characterised by increased risk of developing melanoma
- caused by missense or nonsense mutations in CDKN2A (most common) or CDK4 genes
- The CDKN2A is a tumour suppressor gene that encodes for regulators of the cell cycle (alternative splicing of this gene gives either p16 or p14 that are important regulators of the cell cycle by inhibiting the activity of CDKs).

Question 14

True or false: melanoma only affects the skin?

Answer 14

False, melanoma affects anywhere melanocytes can be found (including uveal (eyes), cutaneous, pancreas and neuronal)

Question 15

How do mutations in the CDKN2A gene cause melanoma?

Answer 15

p16 gene product is responsible for inhibiting CDK4/6 so it is no longer able to phosphorylate Rb, so E2F remains unbound and active and can promote transition from G2 to S phase.

p14 gene product inhibits HDM2 that would normally ubiquitylate p53 for proteasomal degradation so p53 remains active and can promote apoptosis. A mutation in p14 means that HDM2 is not inhibited, so p53 is constantly ubiquitylated and degraded, leading to inhibition of apoptosis and uncontrolled cell proliferation.

Question 16

How can gene-environment interaction modify risk of developing cancer?

Answer 16

Risk factors can co-interact and increase risk

Question 17

Explain how UV exposure promotes melanin production under normal circumatances

Answer 17

UV exposure activates causes DNA damage in keratinocytes that results in activation of the TP53 pathway.
As part of the repair mechanism, alphaMSH hormone is produced by the keratinocytes, which binds to the MC1R receptor of the local melanocytes.
This results in activation of cAMP/CREB signalling pathway and upregulation of pigment genes
Increased production of melanin in melanocytes which are transferred to the keratinocytes.
The melanin is taken up by the keratinocytes and absorbs UV to protect the nucleus from UV.

Question 18

Which type of UV radiation is most responsible for DNA damage and how does this damage occur?

Answer 18

UVA radiation
- able to penetrate further down into the skin
- causes DNA damage indirectly by the production of ROS

Question 19

How does UVB radiation cause DNA damage?

Answer 19

UVB radiation directly causes DNA damage in keratinocytes and melanocytes by the formation of thymine dimers that result in kinks within the DNA and are less able to be accessed and read by DNA polymerase during replication resulting in mutations.

Question 20

Give two examples of driver mutations associated with the development of melanoma

Answer 20

• BRAF
• NRAS
• RAC1
• STK19
• PPPEC

Question 21

Give three examples of events that promote melanoma progression after acquiring a driver mutation?

Answer 21

• Failure of DNA repair mechanisms
• hyperactive RAS/RAF/MEK/ERK signalling pathway (proliferation)
• Hyperactivation of the PI3K/ATK/mTOR pathway that promotes differentiation and proliferation.

Question 22

What is the Fitzpatrick scale?

Answer 22

I-VI scale classifying pigmentary prototypes (I being the lowest amount of epidermal melanin and IV having the greatest amount of epidermal melanin)

Question 23

How does the Fitzpatrick scale relate to UV phenotype and melanoma risk?

Answer 23

I = are more UV sensitive and tend to burn rather than tan
up to
IV = are more UV resistant and tend to tan and never burn

The lower the classification on the Fitzpatrick scale, the more increased risk of melanoma (this risk decreases as the scale goes up with VI having the lowest risk)

Question 24

Why do people with red hair, fair skin and freckling (RHC variants) more at risk of DNA damage and melanoma development?

Answer 24

These RHC variants are associated with five SNPs that result in a hypomorphic phenotype.
This means their M1CP receptors have some partial loss of function that makes them less effective at signalling.
This results in reduced production of eumelanin and more pheomelanin produced thus increased DNA damage