10: Oncogenes and TS-genes Flashcards
1
Q
What are the hallmarks of cancer?
A
- resisting cell death
- sustaining proliferative signalling
- evading growth suppressors
- activating invasion and metastasis
- enabling replicative immortality
- inducing angiogenesis
AND: - deregulating cellular energetics
- avoiding immune destruction
- tumour-promoting inflammation
- genome instability and mutation
2
Q
Cell cycle - summary of controls
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.
3
Q
Cycle checkpoints
A
- M: check for chromosome attachment to the mitotic spindle
- G1: restriction pointL check for cell size and favourable environmental conditions
- G2: check for damaged or unduplicated DNA; check for unduplicated centrosomes.
4
Q
What are proto-oncogenes? How are they different to 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.
5
Q
Oncogene activation
A
- normal proto-oncogene
- mutation on the coding sequence (point mutation or deletion, etc.) -> aberrantly active protein
- Gene amplification -> multiple gene copies = overproduction of normal protein (e.b. in breast cancer Her2)
- Chromosomal translation (chimeric genes) -> string enhancer increases normal protein levels e.g. Burkitt;s lymphoma
OR
insertional mutagenesis (e.g. viral infection) -> fusion to actively transcribed gene overproduces protein or fusion protein is hyperactive e.g. bcr-abl Philadelphia chromosome. - you can have a promoter put in front of a gene that is not usually expressed.
6
Q
Philadelphia chromosome
A
- 9;22
- BCR-ABL
- ABL: proto-oncogene
- BCR: ?
- seen in CML
7
Q
Slide 12 genes
A
- met; neu (her1,2,3 are part of the neu group) part of phosphorylation tag
- src; ret; [art of phosphorylation tag
- ras; pim-1;
- Myc; fos; jun;
8
Q
Mutant RAS aberrant activity
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.
- this leads to increased Raf and activation of downstream pathways such as ERK and therefore proliferation and survival.
9
Q
What are some common oncogenes in human tumours?
A
- SRC
- MYC
- JUN
- Ha-RAS
- Ki-RAS
=> see slide 15 for more info
10
Q
What are tumour suppressor genes?
A
- Typically proteins whose function is to regulate cellular proliferation, maintain cell integrity (e.g. RB -> one of the important parts of the G1-S checkpoint)
- Each cell has two copies of each tumour suppressor gene.
- Mutation or deletion of one gene copy is usually insufficient to promote cancer.
- Mutation or loss of both copies means loss of control.
- keep in mind haploinsufficiency: sometimes one mutation os enough to have the phenotype)
11
Q
Knudson’s two hit hypothesis
A
- For hereditary cancers people already have an inherited mutation and then acquire a mutation later on -> you have to be unlucky once.
- In sporadic cancer, you have to be unlucky twice.
- Haploinsufficiency: in some diseases one mutation is enough to drive the phenotype.
12
Q
Inherited cancer susceptibility
A
- discovery of TS-genes
Features:
- Family history of related cancers (e.g. to get tested for BRCA you have to have a fair history of breast cancer in the family)
- 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.
13
Q
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.
=> lots of families with multiple cases; linked to Cdks.
14
Q
Functional classes of TS-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
=> Suppress the neoplastic phenotype
+ fit in well with the hallmarks of cancer.
15
Q
What are some common tumour suppressor genes that may be mutated in cancer?
A
- p53 (very difficult to target in cancer therapy because it has so many different roles)
- BRCA1 (important for single strand break repair)
- PTEN
- APC
- p16-INK4A
- MLH1
16
Q
p53
A
= guardian of the genome
- 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.
- bound to MDM2 (mitotic regulator) -> inactive; if released it has actions including metabolic homeostasis, antioxidant defence, DNA repair, Growth repair, senesc, apoptosis
17
Q
APC tumour suppressor gene
A
- e.g. familial adenomatous polyposis coli
- Due to a deletion in 5q21 resulting in loss of APC gene (tumour suppressor gene).
- Involved in cell adhesion and signalling.
- Sufferers develop multiple benign adenomatous polyps of the colon.
- There is a 90% risk of developing colorectal carcinoma.
- 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.
18
Q
What are the steps in the development of colorectal cancer?
A
Hyperplasia (Apc) -> (Metaplasia,Dysplasia) Adenoma (k-ras) -> carcinoma (p53) -> metastasis
19
Q
What are the differences in oncogenes and ts-genes in cancer?
A
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 tumour
20
Q
How many driver mutations are needed in cancer?
A
- depends on the type, e.g. colon needs about 11, kidney 2, breast and stomach 4, lungs and brain need 6.
21
Q
What is a driver mutation?
A
a mutation that gives a selective advantage to a clone in its microenvironment, through either increasing its survival or reproduction. Driver mutations tend to cause clonal expansions.
22
Q
COSMIC
A
- catalogue of somatic mutations in cancer.
- important for precision medicine.
23
Q
Summary
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.
24
Q
What is special about p53?
A
- it is a tsg
- its mutants act in a dominant manner and mutation of a single copy is sufficient to get dysregulation of activity
- bad to target in cancer therapy because it has so many important roles and important effects in healthy cells
25
Q
Have does a p53 mutation affect the cancer prognosis?
A
poor prognosis
- usually FH, aggressive, strange rare tumours.
26
Q
What does p53 do?
A
Responds to: - NO - oxidative stress ribonucleotide depletion - mitotic apparatus dysfunction - oncogene actovation - DNA replication stress - double strand breaks - telomere erosion
By:
- apoptosis
- antioxidant defence
- metabolic homeostasis
- DNA repair
- growth arrest
- senescence
27
Q
MDM2 and p53
A
- MDM2 is bound to p53 -> inactive
- regulated
- self regulation
28
Q
MDM2 and p53
A
- MDM2 is bound to p53 -> inactive
- regulated
- self regulation
29
Q
typical progression to CRC
A
normal -> APC mutation -> hyper proliferative epithelium -> Kras -> Adenoma -> p53 -> carcinoma
