Oncogenes and Tumour Suppressor Genes Flashcards
6 hallmarks of cancer
SPINAP
Self-sufficient (Sustaining proliferative signalling)
Pro-invasive + metastatic
Insensitive to anti-growth signals
Non-senescent (Enabling replicative immortality)
Anti-apoptotic
Pro-angiogenic
What is gene amplification?
Production of multiple gene copies
overproduction of normal protein
What are chimeric genes?
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= Chromosomal translocation)
When can the formation of chimeric genes be a problem?
- If 1 of the pieces of translocated DNA is a promoter, it could lead to upregulation of another gene portion (e.g. in Burkitt’s lymphoma)
- If the fusion gene codes for an abnormal protein that promotes cancer
What is the Philadelphia Chromosome?
Chromosome produced by the translocation of the ABL gene on chr 9 (promotor) to the BCR gene on chr 22 (anti-apoptotic)
The BCR-ABL fusion gene encodes a protein that promotes development of cancer
State 5 important oncogenes in human cancers and their functions
SRC: tyrosine kinase Myc: transcription factor JUN: transcription factor Ha-Ras: membrane bound GTPase Ki-Ras: membrane bound GTPase
What is an example of an inherited cancer?
Retinoblastoma: malignant cancer of the developing retinal cells
What mutation causes retinoblastoma?
RB1 TSG
on Chr 13q14
What are the 8 functional classes of tumour suppressor genes?
Regulate cell proliferation Regulate cell growth Regulate cell cycle Maintain cellular integrity Nuclear transcription factors DNA repair proteins Cell adhesion molecules Cell death regulators All these functions suppress the neoplastic phenotype
State 4 important tumour suppressor genes in human cancers
P53: cell cycle regulator
BRCA1: cell cycle regulator
PTEN: tyrosine + lipid phosphatase
APC: cell signalling
In what form is p53 inactive?
When it is bound to MDM2
What is p53 important for?
Regulation of p53 target genes (involved in DNA repair, growth arrest, senescence etc.) + protein-protein interactions (e.g. apoptosis)
What is odd about p53 considering it is a tumour suppressor gene?
It acts in a DOMINANT manner: mutation of a single copy is sufficient to achieve dysregulation of activity
What deletion causes loss of the APC gene?
5q21
What is APC involved in?
Cell adhesion
Cell signalling
What is the risk of people with loss of 5q21 developing colon cancer?
90%
What signalling pathway is APC involved in?
WNT signalling
What is the main role of APC that prevents uncontrolled growth?
Breaks down beta-catenin so that it doesn’t bind to LEF1 + promote uncontrolled proliferation
Describe the step-by-step development of colorectal cancer.
APC mutations –> hyperproliferative epithelium
DNA hypomethylation + K-ras mutation cause polyp formation–> adenomas
P53 mutation will result in the development of carcinoma
What are the 4 emerging hallmarks of cancer?
DIE U Dysregulated metabolism (less dependent on aerobic resp.) Inflammation Evades immune system Unstable DNA
What do proto-oncogens code for?
Essential proteins involved in maintenance of cell growth, division + differentiation
How is a protein product coded for by an oncogene different to that coded for by a proto-oncogene?
Protein no longer responds to control influences
In what ways can oncogenes be expressed?
Aberrantly expressed
Over-expressed
Aberrantly active
What is required to convert a proto-oncogene to an oncogene?
A single mutation
How could a viral infection convert a proto-oncogene to an oncogene?
Insertional mutagenesis
How is mutant Ras different to normal Ras?
Normal Ras becomes active on binding GTP
Dephosphorylation to GDP switches Ras off
Mutant Ras fails to dephosphylate GTP + remains aberrantly active
What is the function of tumour suppressor genes?
Regulate cellular proliferation + maintain cell integrity
Each cell has 2 copies of each TSG
What has to happen to tumour suppressor genes to cause cancer?
Mutation of both copies of a TSG results in loss of control
What is haploinsufficiency?
Where 1 mutated copy of a TSG is sufficient to promote cancer
What does Knudson’s 2 hit hypothesis show?
Sporadic cancer: Requires two acquired mutations of the same gene
Hereditary cancer: Requires an acquired mutation to a TSG that already has 1 inherited mutant form
What are 6 features of inherited cancer susceptibility?
FH of related cancers Unusually early age of onset Bilateral tumours in paired organs Synchronous/ successive tumours Tumours in different organ systems Mutation inherited through germline
Describe the state, mutations required, specificity and types of cancer associated with oncogenes
Gene active in tumour Specific translocations/ point mutations Mutations rarely hereditary Dominant at cell level Broad tissue specificity Leukaemia + lymphoma
Describe the state, mutations required, specificity and types of cancer associated with tumour suppressor genes
Gene inactive in tumour Deletions or mutations Mutations can be inherited Recessive at cell level Considerable tissue specificity Solid tumours
