Cancer Genetics Flashcards
Heritable Cancers
- Some cancers have a heritable component.
- BRCA1,2 genes linked to susceptibility to breast cancer
Complexity of Cancer Genetics
- Found 23k mutations in the lung cancer genome, mostly due to exposure to chemicals in tobacco smoke
- Melanoma, ~70% were associated with UV damage
Benefits of genomic analysis of cancer
- Provided a list of potential therapeutic targets for future drug development and for personalising cancer therapies
Mutation hotspots
Regions more likely to be mutated than others
No mutation hotspots in most tumour suppressor genes - likely to be because many mutations will lead to an inactive protein(TS genes) but only a few specific mutation will produce an active protein(Oncogenes)
Genetics of metastasis
Metastatic tumours generally have a higher mutational burden than primary tumours they originate from. Reflects the complexity of the metastasis process and the need for additional mutations as well as genetic divergence following dispersal
Molecular typing of cancer
Cancers are usually categorised based on
their tissue of origin
Can mask their complexity, Lymphoma is over a dozen diseases that are characterised by either the cell type they originate in or some phenotypic property
Epigenetic regulation of Cancer
Understanding the
mutations linked to
cancer is not sufficient to
understand the disease.
Changes in gene
expression are just as
important, so
transcriptomics are
needed in addition to
genomic data.
Personalised Medicine: Mercaptopurine
Used to treat lymphoblastic leukaemia, but in some can cause severe haematotoxictity
The required doses and risk of Adverse Drug Reaction (ADR) to mercaptopurine has
been associated to polymorphisms in the thiopurine S-methyltransferase (TPMT)
enzyme. TPMT catalyses the S-methylation of mercaptopurine, inactivating it. Pharmacogenomics can be used to predict patients responses to mercaptopurine.
Personalised Medicine: Herceptin
- Expensive
- Monoclonal antibody that binds to epidermal growth factor 2 receptor (Her2) blocking cell growth
- To be effective HER2 expression must be increased in the breast cancer
Intratumour Genetic Heterogeniety
Ubiquitous mutations are found in all parts of the tumour which suggests they arose early in its development.
Shared primary mutations are found throughout the primary tumour but not in the metastasis suggesting they emerged later, after some cells had spread
Shared metastasis mutations arose after metastasis showing genetic divergence from the primary
and suggesting genes that might be important in facilitating metastasis
Response to therapy
A genetically diverse tumour may require multiple different treatments each targeting a
different sensitivity.
However treatments targeting a particular sensitivity creates a strong selection pressure that can lead to the emergence of a resistant phenotype following additional genetic alterations.
