Genetics - Bone Pain Flashcards
Carcinogenesis
The description of how a normal cell evolves into an invasive cancer cell
Changes to make the cell tumourgenic
Immortilisation
Indepence of expression growth factors - fails to follow normal growth constraints
Invasion of the underlying basement
Hallmarks of cancer
Evading growth suppressors Avoiding immune destruction Enabling replicative immortality Tumour-producing infl Activating invasion and metastasis Inducing angiogenesis Genome instability and mutation Resisting cell death Deregulating cellular energetics Sustaining proliferative signalling
Important heritage (cell to cell) changes
Dominant driver mutations in oncogenes
Recessive driver mutations in tumour suppressor genes
Epigenetic changes
The gene is not altered in DNA sequence
Changes leading to functional changes in the operation of the cell
A protein might be over expressed or under expressed
A protein might change its function
It might produce a change in the regulation of a pathway
Types of mutations
Substitution Deletion Insertion Copy number change Break points/ chromosomal rearrangement
Oncogene products
Involved in pathways that regulate growth
Usually has a lack of regulation (cell growth factor independent) or increased activity
Converting proto-oncogene –> oncogene
Point mutation or deletion
Gene amplification events
Chromosomal rearrangement – involving breakage and re-joining of the DNA helix
Loss of TSG
Loss of the gene and its protein products will be a big problem for maintaining normal cell growth controls
Genetics in the diagnosis and management of cancer
Diagnosis
Subtype classification
Prognostic info
Monitoring treatment response (detection of minimal residual disease)
Rational drug design (e.g. tyrosine kinase inhibitors)
Stratification of treatment regimes based on genetics (actionable somatic driver mutations)
Carcinogens (initiators and promoters)
Tobacco smoke Ionising radiation Sunlight Aflatoxin Alcohol, asbestos, benzene, bracken, charred foods, creosote, diesel fumes, dioxins, radon, formaldehyde, saccharin, tar, HPV, human T-cell lymphotropic virus, etc
What happens when there is a germline mutation or deletion of one allele of a TSG
Inactivation or
Deletion of the other allele
What TSG is frequently inactivated in malignancies
TP53 - ‘guardian of the genome’
Can cause cell cycle arrest
Li Fraumeni Syndrome
Rare, autosomal disorder
Predominance of sarcomas, breast cancers, brain tumours and adrenocortical carcinomas
Caused by inherited mutations of TP53
