Genetic Pathways in Cancer

Question 1

Give some examples of components of the dynamic gradient involved in growth control of the colonic mucosa

Answer 1

• APC

- Wnt

Question 2

What are five mechanisms by which growth control can be mediated?

Answer 2

• Levels of secreted growth factors
• Levels of secreted growth inhibitors
• Environmental growth inhibitory factors
• Intrinsic program of differentiation/apoptosis
• Tumour immune response

Question 3

What are the 6 hallmarks of cancer?

Answer 3

• Self sufficiency in growth signals
• Insensitivity to anti-growth signals
• Evading apoptosis
• Limitless replicative potential
• Sustained angiogenesis
• Tissue invasion and metastasis

Question 4

What does the adenoma-carcinoma sequence describe?

Answer 4

Histological evolution of colorectal cancers

Question 5

What does the Fearon-Vogelstein model describe?

Answer 5

Genetic basis of tumour evolution

Question 6

What are the 4 steps involved in genetic evolution of colorectal cancer (=adenoma-carcinoma sequence)?

Answer 6

• Step 1: mutation in APC gene (normal to early stage adenoma)
• Step 2: mutation in KRAS2 (larger adenoma)
• Step 3: mutation in 18q genes (e.g SMAD; high grade adenoma)
• Step 4: mutation in TP53 (becomes invasive)

Question 7

Does the sequence of occurrence of the mutations tend to be maintained?

Answer 7

Yes (e.g. APC earlier, TP53 later)

Question 8

Mutations occur randomly but, for example, we see APC mutations more. When are gene mutations selected for?

Answer 8

• When they give maximal growth advantage resulting in waves of clonal expansion
• if you had mutations in genes A-E, you may get a better growth advantage in gene C and therefore this will outgrow the others (=clonal expansion)
• then, mutations randomly occur again in those with gene C and have further mutations in genes A-E and it is C/A that grow faster and we see clonal expansion of this combination and so on

Question 9

Do oncogenes cooperate?

Answer 9

Yes - mutation more likely to be selected if it interacts better with earlier mutations

Question 10

A tumour contains several mutations - are all the mutations necessary for retention of the tumour characteristics?

Answer 10

• If a mutation is essential = oncogene addiction

- if a mutation is not essential = oncogene amnesia

Question 11

What is synthetic lethality?

Answer 11

• presence of a mutation causes dependence on another non-mutated gene
• inhibition of non-mutant gene will cause apoptosis (but only in presence of mutant gene)
• if synthetically lethal partners can be identified then you can target and kill the tumour cells whilst leaving normal cells untouched
• e.g. PARP inhibitors in tumours with BRCA1 mutation

Question 12

What are the issues with functional pathways in cancer genetics?

Answer 12

• Normal cellular or physiological functions involve several genes - they may be disrupted at more than 1 point (e.g. PI3K pathway)
• some pathways will only be disrupted at 1 point (e.g. BRAF/KRAS mutations are mutually exclusive)
• mutation of different genes may disrupt the same function (e.g. loss of any one of four mismatch repair genes in tumour with MSI)