Molecular basis of cancer Flashcards
Types of mutation
Point mutations -change in amino acid -frameshift -introduce STOP codon -change splicing Gene amplifications Chromosomal translocations
Characteristics of cancer cells
Excess proliferation without external stimuli
Loss of control mechanisms
Loss of apoptosis
Defects in DNA
Irreversible, limitless change
Acquisition of blood supply - angiogenesis
-invasion of surrounding structures
What do cancer cells always have?
Mutations in genes
Mutations in DNA can lead to changes in levels or function of gene product
In one base happen all the time and leads to
- can change sequence of mRNA
- this can change tRNA but often won’t
- this can change amino acid, but probably not
Frameshift
Point mutation, one base chopped out (e.g. by sunlight)
Causes a big problem
Changing every tRNA, because all bases afterwards are shifted along
Amplification
Entire section of chromosome, or duplication of chromosomes
e.g. Her2 becomes overexpressed if amplified, so cell divides much more than it should
Chromosomal translocation
Happens in fertilisation and development but should not neo-natally
E.g. chrosome 9 and 22 swap a bit
-fusion protein with tyrosine kinase activity so transcribed a lot more
-Philadephia chromosome
Somatic mutation
Occur in nongermline tissues
Nonheritable
Germline mutations
Present in egg or sperm
Are heritable
Cause cancer family syndrome
Can not affect the person who originally gets mutation but child could be affected
Dark matter of cell
Most RNA does not encode protein, nor is it directly involved in protein synthesis
Non-coding RNA
-miRNA
-IncRNA
-antisense
A lot of this has functions! So not just protein coding that causes cancer
Causes of somatic mutations
Diabetes
Lung cancer
Genes involved in cancer
Oncogenes Tumour suppressor genes Apoptosis genes Mismatch repair genes -these groups overlap a lot
Oncogenes
Give signal to divide (G1)
Accelerator for cell proliferation
Promote autonomous cell growth and proliferation
> expression (activation) in malignancy
Tumour suppressor genes
Tell cell to stop dividing (S)
Brake to cell prolliferation
Loss of expression (gene deletion) or function (mutations) in malignancy
DNA repair genes
Recognise mutations within DNA and repair them
After S
What do oncogenes code for?
Growth factor and their receptors, signal transducers and cell cycle components
Normal function of oncogenes
Proto-oncogenes
Normal function in controlling cell proliferation and cell division
What do tumour suppressor genes code for?
Code for factors which control cell cycle, regulate apoptosis, transcription or cell interactions
Normal function of tumour suppressor genes
Suppressing cell proliferation and maintaining tissue integrity
Two hit hypothesis
Hit 1: inherited loss of gene on one chromosome +
Hit 2: sporadic loss on second chromosome
–> cancer
Two hit hypothesis examples
Retinoblastoma
Apoptosis genes
Genes that regulate normal cell death. May see
> activity of gene which inhibits apoptosis
< activity of genes which promote apoptosis
BCL-2 overexpressed in lymphomas
Mismatch repair genes
Code for enzymes important for repair of damaged DNA
-DNA damage common due to environmental carcinogens
Loss of expression (deletion) or function (mutation) in malignancy
> risk of mutations & activation or loss of oncogenes & tumour suppressor genes
Factors in carcinogens
Genetic e.g. somatic
Environmental e.g. sunlight
Chemicals e.g. nitrosamines (tobacco)
Viruses e.g. HPV
Multistage carcinogens
Normal cell –> activation of oncogenes/ supression of TSG/ faults in DNA repair –> precancer –> multiple genetic events –> cancer
Bowel carcinogenesis
Normal –> hyperplasia –> adenoma –> Carcinoma –> metastasis
Oral cancer carcinogenesis
Normal –> patch –> field –> aneuploid –> tumour –> metastasis
Epigenetics
-chemical changes to DNA
-often occur because of environmental factors, age etc.
-increasingly thought to be important in cancer
E.g. methylation in wrong place
The tumour microenvironment
First stops tumour
Then can corrupt and spread it
