Molecular basis of cancer

Question 1

4 classes of genes that are the principal targets of cancer causing mutations

Answer 1

1. Proto-oncogenes (growth promoting)
2. Tumour suppressor genes
3. DNA repair genes
4. Apoptosis-regulating genes

Question 2

What are the 8 hallmarks of cancer?

Answer 2

8 fundamental changes in cell physiology

1. Self-sufficiency in growth signals
2. Insensitivity to growth -inhibitory signals
3. Altered cellular metabolism
4. Evasion of apoptosis
5. Limitless replicative potential (immortality)
6. Sustained angiogenesis
7. Ability to invade and metastasize
8. Ability to evade the host immune response

Question 3

Proto-oncogenes include

Answer 3

1. Growth factors
2. Growth factor receptors
3. Signal transducers
4. Transcription factors
5. Cell cycle proteins

Question 4

Most important kind of growth factor receptor?

Answer 4

Tyrosine kinase receptor

Question 5

Give examples of the 3 kinds of oncogenic mutation in growth factor receptors

Answer 5

1. Point mutation in ERBB1 results in constitutively activated EGFR in lung cancer
2. Amplification of ERBB2 results in constitutively activated HER2 receptor in breast cancer
3. Gene rearrangement resulting in EML4-ALK fusion receptor causes constitutive activation of the ALK tyrosine kinase receptor in lung adenocarcinoma

Question 6

Tyrosine kinase receptor activation activates what signal transducer?

Answer 6

RAS

Question 7

What are the two different arms activated by RAS?

Answer 7

1. RAS-RAF-MAPK-MYC-D cyclins

2. RAS-PI3K-AKT-mTOR

Question 8

T or F: activated RAS can completely substitute for receptor tyrosine kinase activity

Answer 8

True

Question 9

What is the most common type of RAS mutation?

Answer 9

Point mutation

Question 10

What family of proteins does RAS belong to?

Answer 10

Membrane associated G proteins

Question 11

What do GAPs do?

Answer 11

GAPs are GTPase activating proteins. Once activated, RAS has intrinsic GTPase activity that dephosphorylates GTP (causing RAS activation) to GDP (causing RAS inactivation). GAPs amplify this intrinsic GTPase activity by more than 1000-fold, terminating signal transduction by RAS and preventing uncontrolled RAS activity.

Question 12

Give an example of a GAP that is mutated in a familial tumour syndrome

Answer 12

NF1 - Neurofibromin 1 - is a GAP that is mutated in neurofibromatosis type 1.

Question 13

What are the functions of AKT?

Answer 13

1. Activate mTOR - a sensor of cellular nutrient state, which when activated stimulates protein and lipid synthesis
2. Inactivate pro-apoptotic molecules BAD and FOXO

Question 14

What is the function of PTEN?

Answer 14

Inhibit actions of PI3K

Question 15

T or F: nonreceptor tyrosine kinases activate different pathways to receptor tyrosine kinases

Answer 15

False

Question 16

Give an example of a nonreceptor tyrosine kinase proto-oncogene

Answer 16

ABL on chromosome 9. A BCR-ABL translocation results in consititutively activated ABL and chronic myeloid leukaemia.

Question 17

Give an example of a nonreceptor tyrosine kinase proto-oncogene point mutation.

Answer 17

JAK2 - relieves the normal dependence of haemopoietic progenitors on signalling by growth factors such as erythropoietin.

Question 18

The transcription factor most commonly involved in human tumours is?

Answer 18

MYC

Question 19

Mechanisms by which MYC promotes neoplastic cell growth?

Answer 19

1. Activate D cyclins which cause progression through cell cycle past the G1/S restriction point
2. Enhance ribosome assembly
3. Induce metabolic reprogramming and the Warburg effect
4. Upregulate expression of telomerase
5. Reprogram somatic cells into pluripotent stem cells

Question 20

Why are defects in the G1/S checkpoint more important in tumorigenesis than defects in the G2/M checkpoint?

Answer 20

Defects in the G1/S checkpoint lead not only to growth dysregulation but predispose to the mutator phenotype.