Neoplasia 2 Flashcards
1
Q
What are the 4 classes of normal cell regulatory genes that are targets of genetic damage in carcinogenesis?
A
- growth-promoting proto-oncogenes
- growth-inhibiting TSGs
- genes that regulate apoptosis
- genes involved in DNA repair
2
Q
What is required to promote carcinogenesis in terms of oncogenes and TSGs?
A
- only 1 allele of oncogenes needs to be activated/mutated
- 1 must remain functional, activated dominates over its normal function
- both alleles of TSG must be affected to lose TS function
- TS functioning is completely lost; can still get TS function with 1 allele
3
Q
What types of mutations occur in cancer?
A
- errors in DNA replication that are not repaired
- DNA repair genes eg BRCA1 & 2 are damaged, leads to accumulation of errors
- hotspots for mutation are oncogenes and TSGs or their regulatory regions
- point mutations
- activate oncogenes
- inactivate TSGs
- amplifications of oncogenes
- chromosomal rearrangements/translocations
4
Q
BRCA1, BRCA2
A
- DNA repair genes, familial breast cancer
- mutation causes inability to repair mutated DNA and tf accumulation of errors
5
Q
Her2-neu
A
- oncogene, breast cancer
6
Q
Ras
A
- oncogene
7
Q
Myc
A
- oncogene
- N-Myc –> neuroblastoma, small cell carcinoma of lung
- L-Myc –> small cell carcinoma of lung
8
Q
p53
A
- TSG
- mutation causes Li Fraumeni syndrome (various tumours)
- normal function is to drive cells towards cell cycle arrest/apoptosis, directs DNA repair
- mutation causes loss of regulation of apoptosis
- activated by cellular stresses: DNA damage, oncogenes, hypoxia, NT depletion, telomere erosion
- functions in S (synthesis) phase of cell cycle, inhibited by oncogenes
9
Q
Rb
A
- TSG - first to be identified
- retinoblastoma
- 1/20000 children
- usually inherit (familial) one defective copy, and the other defects by somatic mutation (LOH)
- function in G1 phase of cell cycle
- inhibited by oncogenes (Ras, Myc)
10
Q
p16
A
- TSG
- melanoma
11
Q
APC
A
- TSG
- familial adenomatous polyposis/colon cancer
12
Q
PTEN
A
- TSG
- Cowden syndrome (epithelial cancers)
13
Q
What types of receptors are involved in cell signalling and proliferation control?
A
- tyrosine kinase (growth factors)
- 7TM G-protein coupled receptors
- cytokine receptors (inflammation)
14
Q
What is the most important signal transduction pathway in tumour growth and survival?
A
PI3 kinase (via growth factors acting at tyrosine kinase receptors)
inhibited by PTEN (TSG)
15
Q
What are common oncogenic factors?
A
- growth factors (autocrine loops)
- growth factor receptors
- over-expression or always active
- signal transduction proteins
- intermediates in cascade - G proteins, phosphorylases, kinases
- transcription factors
- cyclins and CDKs
- uncontrolled cell cycle progression
16
Q
How do TSGs act?
A
- directly inhibiting the cell cycle (Rb, p53)
- inhibiting oncogenic pathways (Pten)
17
Q
How are TSGs important in familial cancers?
A
- inheritance of one defective copy of a TSG predisposes to development of tumours
- other copy is lost in somatic mutation
18
Q
What is loss of heterozygosity (LOH)?
A
- loss of normal function of one allele of a given gene in which the other allele was already inactivated
- general genetic feature involving TSGs in the development of cancer
19
Q
What is the role of microRNA (miRNA) in regulating expression of TSGs and oncogenes?
A
- non-coding ssRNA, very small (22 NT)
- in oncogene regulation, targets proto-oncogenes by binding the RNA and influencing protein translation
- this can lead to an overexpression of the onco-protein (less proto-oncogene)
- in TSG regulation, there can be too much miRNA that targets TSGs, resulting in reduced TS protein products
- miRNA is mutated in specific cancers
20
Q
What is epigenetic control?
A
- changes in the genomic structure of the gene not at the level of the nucleotide but through other covalent characteristics of the genome
- most common is DNA methylation around the promoter region
- methylation/demethylation is normally controlled to switch genes on and off
- inappropriate methylation can silence gene expression of TSGs
- this is a heritable trait
21
Q
How do tumour cells evade apoptosis?
A
extrinsic pathway:
- reduction of CD95 (Fas receptor)
- inactivation of death-induced signalling complex by inhibiting FLICE (makes them more active)
intrinsic:
- upregulation of BCL2 (which is anti-apoptotic)
- reduction of BAX (pro-apoptotic) due to loss of p53
- loss of APAF-1
- up-regulation of apoptosis inhibitors
22
Q
How do tumour cells promote immortality?
A
- in cells with disabled checkpoints, DNA repair pathways are inappropriately activated by shortened telomeres, leading to massive chromosomal instability and mitotic crisis
- tumour cells activate telomerase to produce more telomeres and prevent this mitotic catastrophe and thereby achieve immortality
23
Q
What allows tumour cells to escape and metastasize?
A
- abnormal expression of cadherins, beta-catenin, and connexins
- allows tumour cells to escape their local environment
- function of these attachments can also be influenced by cellular signalling pathways eg PI3 kinase pathway
24
Q
Heterogeneous makeup of cancer tumours refers to
A
- within a single tumour, neighbouring regions can be genetically different
- secondary tumours are also genetically different from primary tumours
- function of the cell’s ability to divide and make slight genetic changes due to inborn errors or oncogenic changes
- produces a tumour with subcolonies of tumour cells
- the basis for this heterogeneity is thought to be cancer stem cells (tumour-initiating cells)
- arise from normal adult tissue stem cells, transit amplifying or precursor cells
- have high intrinsic resistence to conventional therapies that target proliferating cells because they divide differently from normal tumour cells
- these cells can survive conventional therapy and cause regrowth;
- heterogeneity is a mechanism from which cancer cells can become resistant to chemotherapeutics, and regrowth of tumours is no longer susceptible
