Cancer 10: oncogenes and tumour suppression

Question 1

What are the hallmarks of cancer?

Answer 1

• resisting cell death
• sustaining proliferative signalling
• evading growth suppressors
• activating invasion and metastasis
• enabling replicative immortality
• inducing angiogenesis
• genome instability and mutation
• tumour-promoting inflammation
• deregulating cellular energetics
• avoiding immune destruction

Question 2

What are the key features of the cell cycle?

Answer 2

• cycle checkpoints
• specific proteins accumulate/are destroyed during the cycle e.g. cyclins, cycle dependant kinases , cycle dependant kinase inhibitors
• permanent activation of a cyclin can drive a cell through a checkpoint

Question 3

What do proto-oncogenes do?

Answer 3

they code for essential proteins involved in the maintenance of cell growth, division and differentiation

Question 4

How can proto-oncogenes be converted to an oncogene?

Answer 4

a single mutation

Question 5

How is an oncogene activated? (4)

Answer 5

• mutation in the coding sequence
• gene amplification
• chromosomal translocation (chimaeric genes)
• Insertional mutagenesis (viral infection)

Question 6

What are chimeric genes?

Answer 6

combinations or portions of one or more coding sequences to form new genes

Question 7

What is the Philadelphia chromosome?

Answer 7

formed from the translocation of segments from 9+22 chromosome
-this leads to a BCR-ABL fusion gene that results in cancer

Question 8

What is the risk of proteins involved in signal transduction?

Answer 8

they are potential critical gene targets

- the activation of proto-oncogenes to oncogenes disrupt normal activity

Question 9

How does mutant RAS have aberrant activity?

Answer 9

normally upon binding GTP, RAS becomes active and the dephosphorylation of GTP to GDP switches RAS off

-mutant RAS fails to dephosphorylate GTP and remains active

Question 10

What are tumour suppressor genes?

Answer 10

proteins whose function is to regulate cellular proliferation and maintain cell integrity e.g. RB

Question 11

How many copies of the tumour suppressor gene are in each cell?

Answer 11

two

• mutation or deletion of 1 is usually insufficient to promote cancer
• mutation or deletion of 2 means loss of control

Question 12

What are the features of inherited cancer susceptibility?

Answer 12

• family history of related cancers
• unusually early age of onset
• bilateral tumours in paired organs
• synchronous or successive tumours
• tumours in different organ systems in same individual
• mutation inherited through the germline

Question 13

Give an example of an inherited cancer

Answer 13

RETINOBLASTOMA

• malignant cancer of developing retinal cells
• sporadic, usually involves one eye
• mutation of the RB1 tumour suppressor gene on chromosome 13q14
• RB1 encodes a nuclear protein that is involved in the regulation of the cell cycle

Question 14

What are the functional classes of tumour suppressor genes?

Answer 14

• regulate cell proliferation
• maintain cellular integrity
• regulate cell growth
• regulate the cell cycle
• nuclear transcription factors
• DNA repair proteins
• cell adhesion molecules
• cell death regulators

Question 15

when is p53 inactive?

Answer 15

when it is bound to MDM2

Question 16

What type of activities is p53 important for?

Answer 16

• regulation of p53 target genes

- protein - protein interactions

Question 17

What is p53 activated by?

Answer 17

cellular stresses e.g. oxidative stress, nitic oxide, hypoxia

Question 18

What is unique about p53?

Answer 18

Even though it is tumour suppressor gene, mutants act in a dominant manner. This means a mutation of a single copy is sufficient to get dysregulation of activity.

Question 19

How does loss of the APC gene occur and what does this result in?

Answer 19

• deletion in 5q21
• involved in cell adhesion and signalling
• sufferers develop multiple benign adenomatous polyps of the colon
• 90% risk of developing colorectal carcinoma

Question 20

What pathway is the APC gene involved in?

Answer 20

• WNT signalling pathway

- negative regulator of beta catenin, preventing uncontrolled cell division

Question 21

What are the steps in the development of colorectal cancer?

Answer 21

• a mutation of the APC gene leads to a hyperproliferative epithelium
• DNA hypomethylation and a mutation in K-ras leads to the polyps developing into an adenoma
• a mutation in p53 will result in the development of a carcinoma
• the carcinoma will then go and metastasize

Question 22

What is the difference between oncogenes and tumour suppressor genes?

Answer 22

ONCOGENE

• gene active in tumour
• specific translocations/point mutations
• mutations rarely hereditary
• dominant at cell level
• broad tissue specificity
• leukaemia and lymphoma

TUMOUR SUPPRESSOR GENE

• gene inactive in tumour
• deletions or mutations
• mutations can be inherited
• recessive at cell level
• considerable tumour specificity
• solid tumours