Cancer Genomics and Lung Cancer Flashcards
What is Chromothripsis?
The shattering of the chromosome, a single catastrophic event.
It is the simulataneous fragmentation of distinct chromosomal regions and the subsequent imperfect reassembly by the DNA repair pathways.
Chromothripsis occurs early in tumour development and leads to cellular transformation by loss of tumour suppressors and oncogene amplifications.
What is the likely mechanism responsible for chromothripsis?
Lagging chromosomes in mitosis form a micronucleus. This is associated with chromosome fragmentation. When the cells divide again, the cells that are contained within the micronucleus will condense prematurely and this will lead to fragmentation.
What is the relevance of chromothripsis in relation to tumour formation?
There may be multiple mutations at the same time. These could disrupt several tumour suppressor genes. It could also generate ongenic gene fusions.
Chromothripsis may be associated with more aggressive tumours.
- in multiple myeloma and AML associated with prognosis
- in neuroblastoma survival rates are worse for tumours that have chromothripsis
In Shh subtype of medulloblastoma chromothripsis is associated with p53 mutations.
- also seen in AML
What are the two broad categories of mutations?
Driver mutations
Tumour initiation and progression
Confer growth advantage
Usually more than one per cancer
Passenger (bystander) mutations
Can provide information about mutational processes
What was the mutation identified in the candidate gene study?
The first aim of the Cancer Genome Project was to sequence candidate cancer genes in all forms of cancer.
Activating mutations in BRAF were found. These occur in 50% of human melanomas.
What is a CIRCOS plot?
A CIRCOS plot is a diagrammatic way of displaying cancer genome sequences.
They can show point mutations, Interchromosomal rearrangement, Intrachromosomal rearrangement and copy-number changes.
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