Neoplasia and Preneoplastic conditions Flashcards
What is Neoplasia?
An increase in the number of cells in a tissue - growth exceeds and is uncoordinated with that of normal tissue
How does Neoplasia differentiate from Hyperplasia?
Growth in Neoplasia never attains equilibrium
What is Carcinogenesis?
Non-lethal genetic damage that contributes to a cell undergoing neoplastic change.
Give examples of chemical carcinogens
Benzopyrenes
Polycyclic hydrocarbons
2-Naphthylamine after liver hydroxylation
Nitrosamines in gastric ca
Cyclophosphamide
Aflatoxins
Arsenic
What is promotion?
Long term exposure which encourages cellular proliferation and is usually not mutagenic.
Give 3 examples of oncogene production
- Translocation
- Amplification
- Structural change
Give an example of a STRUCTURAL CHANGE mechanism of oncogene production
A single point mutation in the ras gene –> inability of the protein to hydrolyse GTP
Signalling activity is therefore permanently switch on producing and oncogenic effect
Give an example of a TRANSLOCATION mechanism of oncogene production
Burkitt’s Lymphoma - myc proto-oncogene is translocated from chromosome 8 to 24 –> leading to permanent expression
CML - abl translocation from chromosome 9 to 22
Give an example of a AMPLIFICATION mechanism of oncogene production
Over-expression of DNA segments - myb oncogene is over expressed in some colorectal and gastric carcinomas
What are proto-oncogenes?
Proto-oncogenes code for proteins involved in cell proliferation, including growth factors and their receptors, signal transducers, and nuclear regulating proteins.
In neoplasia, proto-oncogenes become oncogenes through structural change, chromosomal translocations, or amplification
What are examples of Tumour suppressor genes
- Rb gene - on chromosome 13q14
- p53 gene
- NF1 gene - on long arm of chromosome 17
What is Knudson ‘2 hit hypothesis’?
Describes a theory in neoplasia such as retinoblastoma that can be inherited or sporadic.
→ In the inherited form one gene is already defective in the germ line (the first ‘hit’). The second ‘hit’ is due to a mutation in the second allele.
→ Sporadic mutations involve two ‘hits’ in somatic cells.
Loss of both copies of a tumour suppressor gene is needed for neoplasia to develop
Describe how the retinoblastoma protein (pRB) regulates the cell cycle
- E2F activates transcription of genes involved with DNA synthesis
- pRB binds to and inhibits the activation and transcription of E2F
- pRB can be inactivated by phosphorylation, mutation or viral oncogene bindings
- Cyclin D1 and cdk4 mediate the phosphorylation of pRB
- Cyclin D1/cdk4 complex is most active in the G1 phase of the cycle –> causing phosphorylation of pRB —> release of E24
This allows for the G1 phase to enter the S phase - P16 is a cyclin dependent kinase inhibitor that indirectly prevents phosphorylation of pRB
Where is the p53 gene located?
Chromosome 17p13.1
What is the function of p53
The major functions of p53 is cell cycle arrest ant initiation of apoptosis - in response to DNA damage
What is an example of genes that regulate apoptosis?
BCL/BAX family of genes
Describe how the BCL/BAX genes control apoptosis
Bcl-2 protects cells from apoptosis through the mitochondrial pathway
The apoptosis repressor effects is counteracted by the BAX gene family which induces apoptosis
BCL-2 and BAX can form homodimers and heterodimers.
The ratio of homodimers to heterodimers will determine whether apoptosis occurs or not
What condition is an example of a mutation leading to loss of control of apoptosis
What is the affected gene/mutation?
B cell lymphoma - has high expression of BCL-2
Caused by a translocation t (14:18) producing a fusion between bcl-2 gene and the heavy chain gene
This leads to over expression of bcl-2 protein, enhanced B cell survival and neoplasia
What is genomic instability?
Genomic instability occurs when both copies of these genes are lost; thus they resemble tumour-suppressor genes.
What is a Harmatoma?
Non-neoplastic malformation that consists of a mixture of tissue normally found at a particular site.
What are the 2 main types of Harmatomas?
Haemangioma
Naevi
What are Haemangiomas?
Proliferation of vascular channels with a lobulated growth pattern
These may be capillary haemangiomas or cavernous haemangiomas, the latter of which involve large thick-walled calibre vessels.
Capillary haemangiomas may regress during childhood whereas cavernous haemangiomas do not.
Where could ocular haemangiomas occur?
Eyelid
Orbit
Choroid
Which condition is associated with extensive haemangiomas?
Sturge-Weber syndrome
Classic triad of:
- facial port wine nevus,
- ipsilateral leptomeningeal angiomatosis (LAM)
- glaucoma.
Also ocular haemangiomas
