Cancer progession Flashcards
Describe the Colorectal Adenoma-Carcinoma Sequence
90% colorectal cancers arise from adenomas
Genetic analysis of the adenoma-carcinoma spectrum suggests frequently mutated genes - not invariably sequential mutations, together with
a subset of a large variety of other gene mutations mutations/defects in APC and MSH2/MLH1 can be inherited or acquired (usually MLH1 promoter methylation is the acquired MMR defect)
Loss or mutation of APC induces adenoma formation as a result of a loss of…
orderly cell replication
adhesion
cell migration
“gatekeeper” of adenoma genesis
What happens when APC is inactivated?
induces a change in crypt architecture
replicating cells heap up in the mucosa
secondary “hits” or mutations are made more likely
How does deregulation lead to adenomas?
APC regulates b catenin levels, truncated APC –> deregulation
Nuclear b-catenin is a transcriptional master switch in
intestinal crypts controlling proliferation versus differentiation
How common are the different pathways to colorectal cancer?
Adenoma – carcinoma commonest >95%
Ulcerative colitis- small fraction <0.5%
HNPCC/Lynch- 2-4%
FAP- 1%
What is the main pathway to colorectal carcinoma?
Mutational activation of oncogenes and inactivation of tumour suppressor genes
TSG predominate and mutations in at least 6 different genes are required for malignancy- fewer required for adenomas
Since most of the mutated genes are tumour suppressors where both alleles must be targeted, multiple events are required for progression to carcinoma.
What is a glioma?
- tumours of astrocytes;
- they show a spectrum of abnormality and are graded I-IV on histopathological criteria
- increasing grade increasing mutations
What are the features of a Grade 2 or 3 glioma?
3-4 mutations: the most frequent of which are IDH1/2 & p53 loss
What are the features of a Grade 4 glioma?
6-8 mutations: IDH1/2 mutation Loss of G1-S checkpoint control Loss of p53 regulation Telomerase activation Amplification of growth factor receptor (EGF-R) Loss of PTEN 1p19q codeletion
What is leukaemia?
tumours of the haematopoietic system
classification of leukaemias is based on clinical course & cell maturation (acute or chronic)
the cell lineage (myeloid or lymphoid)
As with other cancers this is a genetic disease where somatic mutation leads to the selection of a mutated clone.
How is leukaemia different to carcinomas?
The gross aneuploidy and multiple chromosome rearrangements characteristic of carcinomas is not seen in leukaemias- specific clonal chromosome abnormalities usually translocations, deletions or inversions
In individual leukaemias there are usually only a few chromosome abnormalities (1-3)
In many leukaemias no chromosome changes can be identified and sequencing is necessary to identify the mutations.
What is the Philadelphia chromosome?
Translocations can occur in introns, between 2 exons, of a particular gene and if they join to exons of another gene then there is transcription of a chaemeric mRNA that can be translated to form a fusion protein.
t(9;22) -> bcr/abl fusion is almost certainly the initiating mutation in CML (Chronic myeloid leukaemia)
How can CML transform to acute myeloid leukaemia?
After a latent period of about 3-4 years other genetic events occur -p53 deletion or mutation -Ras activation -duplication of the Ph+ (multi-step carcinogenesis)
