Oncogenes and Tumour Suppressor Genes Flashcards Preview

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Flashcards in Oncogenes and Tumour Suppressor Genes Deck (18)
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1
Q

List some hallmarks of cancer

A
  • Evasion of apoptosis
  • Angiogenesis
  • Invasion of tissues
  • Disregard of signals to stop proliferating
  • Disregard of signals to differentiate
  • Capacity for sustained proliferation
2
Q

Describe the cell cycle briefly

A
  1. G0 - quiescent phase (not replicating)
  2. Cells stimulated to enter the cell cycle
  3. G1 - duplication or growth of contents of the cell not including the nuclear material and growth in cell mass and size
  4. There is a G1 checkpoint to check that the cell is the right size and there are the favourable conditions to continue e.g. growth factor etc
  5. S phase - chromosomal duplication
  6. G2 phase - cell continues to grow and prepare for mitosis
  7. G2 checkpoint - checks for errors in DNA and mutation / duplication prior to mitosis
  8. Mitosis
  9. Back into interphase / G0
3
Q

What is the significance of cyclin within the cell cycle and what other proteins are involved in the cell cycle?

A
  • Permanent activation of cyclin can drive cells through checkpoints in the cell cycle
  • There is destruction of certain proteins such as cyclin, CDK, CDK inhibitors etc
4
Q

1) What is a proto-oncogene?
2) What is an oncogene?

A

1)

  • Genes that code for maintenance of cell growth, division and differentiation

2)

  • An aberrant form of a proto-oncogene resulting in proteins that no longer respond to control influences and cause cancer development
5
Q

Give 4 mechanisms by which oncogenes can arise from proto-oncogenes - i.e. activation of oncogenes. Give an example in 2 of these

A
  1. Mutation in the coding sequence - either point mutation or deletion
  2. Gene amplification - multiple gene copies of the proto-oncogene so they can now be thought of as oncogenes as their is overexpression of the protein that promotes cell growth and division
  3. Chromosomal translocation (chimaeric genes) - especially a problem if one of the pieces of translocated DNA is a promoter, thereby enhancing expression of the other gene, causing uncontrolled proliferation e.g. in Burkitt’s Lymphoma
  4. Chromosomal translocation (insertional mutagenesis) - fusion gene producing abberant protein e.g. Philadelphia Translocation
6
Q

Describe the role of Philadelphia Translocation in the pathophysiology of some cancers - what is it and what happens?

A
  • Philadelphia chromosome formed from the philadelphia translocation as a result of translocation of sections of DNA from chromosome 9 and 22
  • Forms a BCR-ABL fusion gene which is an oncogene causing cancer
7
Q

What more complex signalling cascade pathway is the Ras pathway part of?

A
  • The MAPK signalling pathway (mitogen activated protein kinase cascade)
8
Q

Describe the physiological actions of Ras, and thus how aberrant mutant Ras can cause cancer

A
  • Ras binds to GTP and upon binding, is activated
  • Note Ras also can dephosphorylate GTP to GDP as an autoregulatory mechanism
  • Ras now interacts with RAF
  • RAF signals by phosphorylation and activates the kinase signalling cascade to promote cellular proliferation
  • Oncogenes for Ras cause aberrant Ras production, there is little dephosphorylation of GTP to GDP so there is plenty of GTP available for Ras to bind to and for it to become activated
  • Lots of Ras activated and can bind RAF which promotes cellular proliferation via the kinase signalling cascade. Due to the XS Ras and therefore XS RAF mediated action, there is overproliferation of the cells - cancer
9
Q

Which mutations result in impaired GTP hydrolysis for the Ras oncogene?

A
  • Mutations at codons 12 (Gly), 59 (Ala) and 61 (Gly)
10
Q

Describe the tissue specificity of Ras mutations in oncogenesis and what is it?

A
  • Tissue specificity - different (aberrant) isoforms of the enzyme can result in oncogenesis unique to different tissues
  • E.g. K-ras in lung, colon and pancreatic cancer while…
  • N-ras in acute myeloblastic leukaemia
11
Q

What do tumour suppressor genes do physiologically - don’t have to detail the different functional categories, just what is their basic function?

A
  • The regulate cell growth and proliferation - the ‘brakes’
  • They also maintain cellular and genetic integrity
12
Q

1) Describe the priniciples of Knudson’s 2 hit hypothesis, sporadic and familial mutation
2) This is relevant in oncogenesis in regards tumour suppression genes or oncogenes - and give one exception?

A

1)

  • In order for oncogenesis to occur, usually in TSGs, you must have mutation in both alleles for a gene
  • These mutations can be familial (germline mutation) which are inherited
  • Or sporadic (somatic mutations)
  • In familial mutation, you inherit one mutated TSG, but do not have cancer yet because the other wild-type gene is still functioning, however if this is also mutated after one sporadic mutation picked up in your lifetime and loss of heterozygosity (i.e. both are now mutated TSGs so LOH as both are now the same), then you develop cancer
  • In sporadic mutations, you must pck up 2 sporadic muations in your lifetime which is unlikely, in order to develop cancer

2)

  • Relevant for TSG cancers
  • Exception = p53 cancers
13
Q

How may the presentation of cancer in people who have had a familial mutation differ from those who require 2 sporadic mutations?

A
  • Earlier onset
  • Bilateral tumours in paired organs
  • Synchronous or successive tumours
  • Tumours in different organs in the same individual
14
Q

Describe the pathophysiology of Retinoblastoma and then discuss briefly how its presentation may differ in those who inherited a germline mutation (familial mutation) and those who had purely sporadic mutations causing the cancer

A
  • Malignant cancer of developing retinal cells
  • Mutated RB1 tumour suppressor gene on the chromosome 13q14
  • RB1 encodes a protein that is involved in regulation of the cell cycle, so an aberrant RB1 will result in an abnormal cell cycle, causing cancer
  • Sporadic disease is usually unilateral whereas familial may also be bilateral or multifocal
15
Q

Describe what activates p53, its physiological actions and how it autoregulates

A
  • p53 is activated in response to DNA damage / cellular stress
  • p53 has the following 4 effects:
  1. DNA repair
  2. Arrests growth at G1 - p21 (Waf1) - binds and inhibits cyclins and cyclin dependent kinases to arrest growth
  3. Promotes apoptosis - via Bax - a member of the Bcl-2 family. If p53 fails to repair the cell, it commits the cell to apoptosis
  4. Promotes transcription - of p21 and Bax and Mdm
  • Inhibits growth by stimulating Mdm2 synthesis, Mdm2 causes degradation of p53 - this is a negative feedback mechanism
16
Q

Describe the pathophysiology of cancers as a result of defect in p53

A
  • p53 is a TSG that has 4 effects: DNA repair, promoting apoptosis, G1 growth arrest, promoting transcription of certain genes
  • If DNA damage occurs and there is also aberrant p53, there is failure in DNA repair by p53 and the cell with damaged DNA is not G1 arrested in the cell cycle either
  • The cell with damaged DNA which may be carcinogenic - mutation or aneuploidy, can then survive and multiply as part of a cancerous line
  • Or it may die as a result of mitotic failure
17
Q

Describe the pathophysiology of cancer as a result of aberrant APC

A
  • APC is a TSG
  • Involved in the WNT - a nuclear signal transduction pathway that results in transcriptional upregulation
  • APC inhibits beta-catenin in the WNT pathway, thereby controlling cell proliferation and growth
  • Aberrant APC results in unchecked cell growth and proliferation
  • THIS DOES NOT CAUSE CANCER ALONE
  • It results only in Familial Adenomatous Polyposis (FAP)
  • FAP predisposes you to developing colon cancer
  • If there is, for example, mutation of a proto-oncogene, colorectal adenoma can develop as a result and if there is also, for example, p53 mutation following this, it develops into a carcinoma (malignant) with metastatic potential
18
Q

How do cancers as a result of oncogenes and aberrant tumour suppressor genes (TSGs) differ in the following terms?…

1) Mechanism (general) of activation / inactivation?
2) Inheritance?
3) Dominant / Recessive?
4) Degree of tissue specificity?
5) Types of tumours / cancer that often result?

A

1)

  • Oncogenes - translocation / point mutations / gene amplification
  • TSG - deletions / mutations

2)

  • Oncogenes - rarely hereditary
  • TSG - can be inherited

3)

  • Oncogenes - dominant
  • TSGs - recessive

4)

  • Oncogenes - broad tissue specificity
  • TSGs - very tumour specific

5)

  • Oncogenes - often leukaemias / lymphomas
  • TSGs - usually solid tumours