molecular pathology of tumours Flashcards
what are 4 properties of malignant cells?
- Disordered proliferation
- Disordered apoptosis
- Disordered differentiation
- Disordered relationship between proliferating cells and surrounding environment (invasion, metastasis, angiogenesis) - this allows them to spread around the body
what kind of process is tumour formation?
it is a multi-step process
clonailty:
what are the 4 steps of clonailty? from mutations to a cancer formation
- a mutation gives one cell an advantage
- a second mutation increases the advantage
- a third mutation increases the advantage further and makes the cell invasive
- this leads to dangerous cell survival, proliferation and invasion
what 2 genes can be altered within neoplasia (tumour growth)
oncogenes and tumour supressor genes
what are oncogenes?
what creates an oncogene?
what does the oncogene stimulate?
- drivers of neoplastic behaviour
- from proto-oncogene into oncogene
a single mutation event in a proto-oncogene creates an oncogene
this activating mutation enables oncogene to stimulate cell survival and proliferation which leads to excessive cell survival and proliferation
what are 3 ways a proto-oncogene can be transformed into a oncogene?
- specific mutation in the coding sequence can create a hyperactive protein made in normal events (typical in colon cancers)
- gene amplification of pro-oncogene, creating protein being greatly over produced due to more copies within the genome (typical in breast cancer)
- chromosome rearrangement within the proto-oncogene, which can result in nearby regulatory sequence cause normal protein to be overproduced or a fusion to an actively transcribed gene produces hyperactive fusion protein
what are 4 functions of an oncogene?
- Growth factor – sis, fibrosarcoma
- Growth factor receptor - HER2, breast cancer
- Signal transducer – ras, colon cancer
- Transcription factor - myc, Burkitt’s lymphoma
what are 4 ways oncogene activity can be increased and therefore lead to the development of tumours?
A. Direct stimulation of cell cycle dependent transcription
B. Increased/activation of growth factor receptors
C. Increased growth factor
D. Interference with intracellular signalling
how are tumour supressor genes affected?
a cell undergoes a recessive mutation event which inactivates tumour supressor gene (causing a loss of function)
this has no effect of mutation in one gene copy however, the second mutation event, inactivates the second gene copy
two inactivating mutations functionally eliminates the tumour surpressor gene, which stimulates cell survival and proliferation
where was tumour suppressor gene first studied?
what is Knudson’s two hit hypothesis?
tumour suppressor gene was first studied in retinoblastoma (cancer within the eye)
Knudson’s two hit hypothesis: normally one is protected by this eye tumour as they have two RB1 genes which prevents a tumour from forming
- One mutational loss of one RB1 gene, then it is usually okay - however, if the other RB1 gene is the same cell or daughter cell, then this causes uni-lateral retinoblastoma
- if there is an inherited absence of one of the paired RB1 genes, then there is a mutational loss of RB1 gene in any retinal cell which leads to a very high risk of bilateral retinoblastoma
why does mutating retinoblastoma drive carcinogenesis?
if Rb is mutated, Rb is no longer able to sit upon the transcription factor and S phase is continued, without going through a checkpoint (the cell remains within the proliferating pathway)
what are the two roles of tumour suppressor genes?
they are gatekeepers and caretakers
how are tumour supressor genes gatekeepers?
gatekeeper💅💅💅
- Inhibit proliferation or promote the death of cells, especially those with DNA damage
- Send negative signals to the cell, so the cell does not divide
how are tumour suppressor genes caretakers?
caretaker
- Maintain integrity of the genome by promoting DNA repair
- Nucleotide excision repair pathway
- Mismatch repair
- DNA double strand break repair
what is p53?
where is it frequently mutated?
p53: master tumour suppressor gene (does both gatekeeping and caretaking)
- p53 frequently mutated in a wide range of different tumours
1. ovary
2. esophagus
3. colorectum
where can defects in p53 be seen?
what is the nature of p53 mutations?
defects in p53 can underlie in familial defects seen above: Li-Fraumeni syndrome
- very high cancer incidence due to defect in p53 gene
nature of p53 mutations:
- a result of a missense (swap on amino acid) is a loss of a function, as it is a tumour suppressor gene
- sequence-specific DNA binding makes up the majority of the gene, in which many missense mutations occur
