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Cancer > Oncogenes and tumour suppressor genes > Flashcards

Oncogenes and tumour suppressor genes Flashcards

1
Q

What were the original 6 hallmarks of cancer

A 
Sustaining proliferative signalling
Resisting cell death
Inducing angiogenesis
Enabling replicative immortality
Activating invasion and metastasis
Evading growth suppressors.
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2
Q

What are the emerging and enabling hallmarks

A

Emerging:
Deregulating cellular energetics- switch to the more energy dependent anaerobic respiration
Avoiding immune destruction.

Enabling:
Genome instability and mutation- to promote mutagenesis that leads to aberrant growth
Tumour-promoting infiltration.

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3
Q

Summarise the key features of the cell cycle

A

Cycle checkpoints (growth arrest ensures genetic fidelity).
Specific proteins accumulate/ are destroyed during the cycle.
Cyclins, cycle dependent kinases, cycle dependent kinase inhibitors
Permanent activation of a cyclin can drive a cell through a checkpoint.

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4
Q

Describe the G1-S checkpoint

A

Check for DNA damage

Restriction point: check for cell size and favourable environmental conditions (growth factor)

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5
Q

Describe the G2-M checkpoint

A

Check for damage or unduplicated DNA

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6
Q

Describe the metaphase checkpoint

A

Check for chromosome attachment to mitotic spindle.

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7
Q

What happens at these checkpoints

A

Cell cycle is arrested
If DNA damaged- tries to repair with DNA repair genes e.g BRCA
If damage too big- apoptosis.

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8
Q

Describe what is meant by proto-oncogenes

A

Proto-oncogenes code for essential proteins involved in maintenance of cell growth, division and differentiation.
Mutation converts a proto-oncogene to an oncogene, whose protein product no longer responds to control influences.
Oncogenes can be aberrantly expressed, over-expressed or aberrantly active.
E.g. MYC, RAS, ERB, SIS
Proto-oncogenes can be converted to an oncogene by a single mutation.

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9
Q

What is the key difference between photo-oncogenes and oncogenes

A

Proto-oncogene: code for essential proteins involved in maintenance of cell growth, division and differentiation e.g. Kinases, phosphorylases, transcription factors

Oncogene: mutations in proto-oncogenes that promote uncontrolled cell proliferation - aberrantly expressed, over-expressed (e.g. HER2) or aberrantly active

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10
Q

Describe how normal photo-oncogenes can be activated

A

The normal proto-oncogene can be activated in 4 ways:
1. Mutation in the coding sequence.
 Point mutation or deletion.
2. Gene amplification.
 A protein may block the DNA polymerase so the polymerase repeatedly backs up to go over the area a few times creating many identical genes.
3. Chromosomal translocation.
 Chimeric genes.
4. Insertional mutagenesis.
 Viral infections – some viruses insert their genome into our DNA and usually this isn’t a problem as much of our DNA does not code but if it’s in a coding region, this could be cancer.

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11
Q

What is the end result of gene amplification

A

You get multiple copies of the protein produced.

Problem with HER2 in Breast Cancers

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12
Q

What are Chimeric genes

A

Genes that are formed by combinations of portions of one or more coding sequence to produce new genes (e.g. the swapping of tips of chromosomes)

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13
Q

When can the formation of chimeric genes be problematic

A

If one of the pieces of translocated DNA is a promoter, it could lead to upregulation of the other gene portion (this occurs in Burkitt’s lymphoma)
If the fusion gene codes for an abnormal protein that promotes cancer

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14
Q

What is the Philadelphia chromosome

A

Chromosome produced by the translocation of the ABL gene on chromosome 9 to the BCR gene on chromosome 22
The BCR-ABL fusion gene encodes a protein that promotes the development of cancer

BCR is anti-apoptotic- so enables tumour to be resistance to stop signals.

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15
Q

Describe the two possible results of chromosomal translocation and insertional mutagenesis

A

Strong enhancer increases normal protein levels
e.g. Burkitt’s lymphoma- lose normal regulation of gene

Fusion to actively transcribed gene overproduces protein or fusion protein is hyperactive.
e.g. Philadelphia chromosome

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16
Q

Summarise the Philadelphia chromosome

A

Philadelphia chromosome: end of long arms of Chr9 and Chr22 exchanged to form the BCR-ABL fusion protein - ABL is a very strong promotor region

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17
Q

Summarise the signal transduction pathways

A

Steroid hormone- Nuclear or cytosolic receptor — transcription/translation — proliferation

Tyrosine Kinase receptor — ligand binds — phosphorylation — proliferation

GPCR- kinase- phosphorylation – proliferaation

Proteins involved in signal transduction are potential critical gene targets (proto-oncogenes)

Activation of proto-oncogenes to oncogenes disrupts normal activity

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18
Q

Give some examples of signal transduction proteins that are photo-oncogenes

A

 Signal transduction proteins are proto-oncogenes.
 Examples:
o Tyrosine kinase receptors EC – met, neu.
o Tyrosine kinase receptors IC – src, ret.
o Transcription factors – myc, fos, jun.
o GPCR g-proteins – ras, gip-2.
o Kinases – raf, pim-1.

May habe a point mutation which changes conformation - so inhibitory proteins cannot bind
or changes phosphorylation residues- such that it’s constitutively active.

The higher up the pathway the mutation is- the harder it is to treat- due to a greater dysregulaiton of downstream pathways.

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19
Q

Describe the aberrant activity of mutant Ras

A

Upon binding GTP, RAS becomes active.
Dephosphorylation of the GTP to GDP switches RAS off.
Mutant RAS fails to dephosphorylate GTP and remains active.

Leading to cell proliferation independent of growth signals

20
Q

Describe some photo-oncogenes and their associated cancers

A

SRC
Tyrosine Kinase
Overexpression/ C-terminal deletion
Breast/colon/lung

MYC
TF
Translocation
Burkitt’s lymphoma

JUN
TF
Overexpression/deletion
Lung

Ha-RAS
G-protein
Point mutaation
Bladder

Ki-RAS
G-protein
Point mutation
Colon/lung

21
Q

Describe Ras signalling

A

o The binding of GTP allows RAS to bind RAF and pass the signal to RAF deliver the signal further to MEK and ERK.

Phosphorylation of Tfs (myc. jun, fos)
Translocation to the nucleus
increasing RNA synthesis and transcription and translation of effector proteins which lead to cell proliferation and cell survival.

22
Q

Summarise tumour suppressor genes

A

Typically proteins whose function is to regulate cellular proliferation, maintain cell integrity.
E.g. RB
Each cell has two copies of each tumour suppressor gene- except in haploinsufficiency- where one mutation is sufficient to produce a tumour
Mutation or deletion of one gene copy is usually insufficient to promote cancer.
Mutation or loss of both copies means loss of control.

23
Q

Describe Knudson’s two hit hypothesis

A

Sporadic cancer : 2 acquired mutations in TSG

Hereditary cancer: 1 inherited and 1 acquired mutation- increased risk of cancer- already have 1 hit

24
Q

Summarise the inherited cancer susceptibility

A 
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.
25
Q

Describe the key features of retinoblastoma

A

Malignant cancer of developing retinal cells.
Sporadic disease usually involves one eye. Hereditary cases can be unilateral or bilateral and multifocal.
Due to 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.
RB1 ensures progression of cell-cycle progression fro G1 – S

26
Q

Describe the functional classes of tumour suppressor genes

A 
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

All with the aim of:
Suppress the neoplastic phenotype

27
Q

What is important to remember about tumour suppressor genes

A

A lot are lethal to the embryo

28
Q

Describe some examples of tumour suppressor genes

A

P53
Cell cycle regulation
Many

BRCA1
Cell cycle regulation
Breast/ovarian/prostate
Singl strand break repair, if overwhelmed- double strand break repair (homologous recombination)

PTEN
Tyrosine and lipid phosphotase
Prostate/glioblastoma and Cowdens syndrome

APC
Cell signalling
Colon

p16INK4A
Cell cycle regulation
Colon

MLH1
Mismatch repair
Colon, gastric

29
Q

Summarise how a cell responds to DNA damage and cellular stress

A 
Detect cellular insult and then switch on genes to repair the cell.
Cellular stresses can include: 
Oxidative stress 
Nitric Oxide 
Hypoxia 
Ribonucleotide depletion 
mitotic apparatus dysfunction 
oncogene activation 
DNA replication stress 
Double-strand breaks 
Telomere erosion

These insults are sensed by the tumour suppressor gene p53
P53 is normally inactivated by a partner protein called MDM2
However, these insults cause MDM2 to be lost, activating p53 and allowing it to act as a transcription factor to turn on gene expression for genes involved in DNA repair

30
Q

Describe the p53 mediated response to mild/physiological stress and severe stress

A 
Mild- regulation of p53 mediated genes involved in:
metabolic homeostasis 
antioxidant defence 
DNA repair 
growth arrest

Severe stress- p53 mediated protein-protein interactions which lead to apoptosis.

31
Q

How many mutations are needed in p53 to get dysregulation of activity

A

Although p53 is a tumour supressor gene, mutants of p53 act in a dominant manner and mutation of a single copy is sufficient to get dysregulation of activity.

32
Q

Why is p53 hard to target in therapy

A

So many ubiquitous roles- would lead to plethora of side effects
Important in healthy cells- side effects
Molecular profiling of tumours to look for mutations - p53 may be driver mutations or passenger mutations-
can’t target p53 to one its functions.

33
Q

describe the importance of p53 mutations in cancer

A

Associated with poor prognosis and family histories of sarcomas and rare tumours.

34
Q

Describe the role of the APC tumour suppressor gene in familial adenomatous polyposis coli

A

Due to a deletion in 5q21 resulting in loss of APC gene (tumour suppressor gene).
Involved in cell adhesion and signaling- MAPK
Sufferers develop multiple benign adenomatous polyps of the colon.
There is a 90% risk of developing colorectal carcinoma- prophylactic colonectomy and regular colonoscopies from teen years

Adenomatous polyposis coli protein

35
Q

What signalling pathway is APC involved in

A

The tumour suppressor gene APC participates in the WNT signalling pathway.
APC protein is a negative regulator of b-catenin, thereby preventing uncontrolled cell division.
Mutation of APC is a frequent event in colon cancer.

Wnt has a stimulatory effect on beta-cantenin

36
Q

Summarise the APC TSG

A

APC TSG: mutation of APC gene causing uncontrolled growth creating polyps, each with increased risk of cancer - becomes almost inevitable
Normal function is to degrade beta catenin (WNT pathway - normally bound to cadherin in adherens junctions)
Mutant APC leads to buildup of beta catenin, leading to binding to LEF-1
LEF-1: complex causes gene transcription

37
Q

What are two features of a normal healthy state

A

Proto-oncogene

Tumour suppressor gene

38
Q

Describe the different combinations that can lead to cell growth and proliferation (uncontrolled) and thus cancer

A

 Cancer can be triggered by:
o Oncogene + TSG.
o Proto-oncogene + defective TSG.
o Oncogene + defective TSG.

39
Q

Describe an analogy that summarises the pathogenesis of cancers

A

Normal genes (regulated cell growth)- TSGs and port-oncogenes in check- car travels at steady speed

1st mutation (susceptible to cancer)- active oncogenes accelerating car- but TSGs acting as brake to halt progression towards cancer

2nd mutation or loss of TSG- accelerates to cancer

40
Q

Outline the development of colorectal cancer

A

Normal epithelium- Apc mutation - leads to hyper proliferative epithelium
This increases the rate of mutations and likelihood go genomic instability:
DNA hypomethylation and k-RAS MUTATION leading to adenoma
p53 mutation then forms carcinoma which can then metastasise

Hyperplasia  Metaplasia  Dysplasia  Carinogenesis

41
Q

What are the two main functions of b-cantenin

A

Functions in cell-cell adhesion (1 mark)

Regulates transcription / gene expression (1 mark)

42
Q

Which protein, defective in familial adenomatous polyposis (FAP), regulates levels of b-catenin by controlling its degradation?

A

The adenomatous polyposis coli protein (1 mark)

0.5 mark for APC

43
Q

Summarise Oncogenes

A

Oncogene

Active in tumours

Translocations/point mutations

Not inherited

Dominant

Leukaemia/lymphoma

Broad tissue specificity

44
Q

Summarise TSGs

A

Oncogene
TSG

Inactive in tumours

Deletions/mutations

Inherited

Recessive

Solid tumours

Tissue specificity

45
Q

Describe the number of mutations needed for each cancer type

A 
Colon- 11
Kidney- 2
Stomach- 4 
Lungs- 6
Breast- 4
Brain -6
46
Q

What is important to remember about cancer

A

Human cancer involves damage to DNA, or inheritance of aberrant sequences, at critical gene targets.
These targets, proto-oncogenes and tumour suppressor genes, regulate cell cycle decisions (mitosis, arrest, differentiation, apoptosis).
The ‘guardian of the genome’, p53 is a key player in decision making during the cell cycle.
Studies of rare heritable cancers have led to an understanding of tumour suppressor genes.
Colon cancer is a model for many of these factors.

47
Q

Summarise the genetic mutations that can cause cancer

A

Genetic mutations causing cancer:
Chromosome translocation
Gene amplification
Point mutations within promotor or enhancer regions of genes
Deletions or insertions
Epigenetic alterations to gene expression

Cancer (15 decks)

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