genetics and cancer Flashcards
what do cells acquire as they divide
mutations
what exists to attempt to fix these mutations
repair mechanisms
what is cancer a disease of
mosaicism largely caused by post-zygotic mutation
gamete → zygote → embryo → human
- Heterogenous
what are driver mutations
Mutations that drive cancer
what are the 2 classes of driver mutations
oncogenes and tumour suppressors
what is a passenger mutation
incidental mutations that happen because the tumour is unstable
what is epigeneics
The study of changes in gene expression without a change in DNA sequence
- DNA methylation
- Interaction with histone proteins
what does methylation do
switches gene off
where does DNA methylation occur
on cytosine bases before guanine bases
what is DNA methylene regarding repair genes
it is deficient DNA repair genes or tumour suppressor genes due to hypermethylation = cancer
what does methylation increase
mutation
describe retinoblastoma
autosomal dominant
Variable penetrance - not everyone with mutation has disease
what is retinoblastoma
a tumour suppressor gene
- Need to lose two copies for tumour to develop
- Both copies can be lost by somatic mutation
what are the methods of gene activation
Duplication of the gene
Activation of the gene promoter
Change in amino acid sequence – active protein configuration
what does activating mutation in BRAF activate
the KRAS pathway
Due to genetic mutation, cancer cells may:
- Produce their own extracellular growth factors
- Overexpress growth factor receptors
- Have active proteins that do not require phosphorylation
how would you activate oncogenes
Activated from proto-oncogenes due to dominant gain of function mutations:
BRAF:
codes for a Raf Kinase protein involved in MAP-K signal pathway
why is the signal always on in point mutation
Point mutation removes the need for phosphorylation - signal is always on
Vemurafenib
BRAF inhibitor HOWEVER easily overcome due to multiple activation pathways for Raf kinase
HER2 in breast cancer:
- amplification results in too many HER2 receptors → increased signal for proliferation
- Trastuzumab binds to HER2 receptors, blocking proliferation signal
Philadelphia chromosome:
translocation which produces a hyperactive fusion protein (BCR-ABL)
what is a tumour suppressors
Genes whose loss (deletions, point mutations) results in carcinogenesis
Retinoblastoma
- pRB - functions at G1 checkpoint
- Mutation in RB gene → loss of function of pRB → retinoblastoma
Two-hit hypothesis
- Mutation of both alleles necessary to inactivate tumour suppressor genes
- The reason cancers are often associated with old age - mutation rates are slow so over a longer time, increased chance of two ‘hits’
Oncogenic signature
- Characteristic of a cancer is determined by its driver mutations
- Cancer cells easily mutate, so quicker evolution of cancer cells
Mismatch repair comple - Lynch syndrome:
hereditary form of cancer due to mutation in mismatch repair gene
Cancer risk
Multifactorial - rarely purely genetic
Features which indicate inherited cancer susceptibility
- Several first/second degree relatives with cancer
- Several close relatives with related cancers
- Unusually early onset
- Bilateral tumours in paired organs
- Tumours in two organ systems in one individual
