Cancer Lecture 5, Inheritance of defects. , Genes that are mutated in…
Cancer Lecture 5
- 2nd leading cause of death worldwide, accounting for 8.8 million deaths in 2015. ( 1 in 6)
- result of normal cells transforming into malignant cells.
- resulting from uncontrolled cell proliferation and resistance to apoptosis ( cell death)
- Originates from a single cell that has acquired a defect.
- will continue to expand a acquire more defects over time
- development of cancer is a multi stage process .
- An example is that in the case of colorectal cancer.
- the adenoma sequencing demonstrates the progression from normal epithelium to small polyps to adenoma to carcinoma.
- changes in cell type.
- from squamous to columnar epithelium.
- which is the case of barrettes oesophagus.
- may be the result of insult. which can then develop into dysplasia.
- increased cell numbers.
- Normal cellular appearances.
- may be due to hormonal stimulation or inflammation.
e.g. benign prostatic hyperplasia.
- displaying increased proliferation, as with hyperplasia
Changes in appearances, large nuclei. loss of tissue architecture.
- malignancy that is no longer under physiological control. not reversible.
Self sufficiency in growth signals.
- Normally cells will require growth factors to promote proliferation.
- Tumours cells produce their own stimulation for growth.
e.g. constitutive active receptors (EGFR)
other proteins downstream of growth factor signalling ((Ras-Raf-Mek pathway)
An example of the EGFR pathway.
- Epidermal growth factor binds to the epidermal growth receptor (EGFR)
- Stimulates downstream pathway to drive cellular proliferation.
Insensitivity to anti growth signals.
- Normal cells enter into the quiescence (Resting phase) until stimulated to proliferate.
- Anti growth signal from neighbouring cells and within the extracellular matrix.
- Disruption of cell cycle proteins enables malignant cells to resist anti growth signals.
Evasion of apoptosis.
- Apoptosis is controlled cell death.
- Overstimulation of proliferation would normally trigger apoptosis.
- Major barrier to cancer initiation.
- In cancer the balance is shifted away from apoptosis.
- resistance most commonly trough the loss of p53 activity or overexpression on anti apoptosis Bcl2.
Limitless replicative potential
- the Hayflick limit-before entering senescence.
- Chromosomes have telomeres at their ends which shorten with each division.
- Cancer cell must be immortalised.
- the activity of telomerase in cancer cells lengthen telomeres and enables limitless proliferation.
- cancer cells have a high demand for nutrients due to increased proliferation.
- to sustain this they must stimulate the production of new blood vessels to provide them with their needs.
- required for tumours to increase significantly in size. but not for disease initiation,
Tissue invasion and metastasis
- Tumours develop the ability to spread to other organs, including distant sites across the body.
- cells need to be able to break out of their environment by the production of extracellular proteases.
- then require to bind to the new environment via cell adhesion molecules (CAMS) and integrins
Highly complex processes.
1954, Armitage and dolls
- used the age distribution of cancers to estimate that carcinogenesis requires 6 out of 7 independent sequential events.
- Concept of carcinogenesis as a
multi-stage process, these events are genetic mutations.
Inheritance of defects.
- In order for a defect to be passed on to its progeny, its must have a genetic or epigenetic basis.
- These changes are known as mutations: parament alteration in DNA sequence.
- which can effect the proteins they encode for. which can later phenotype.
- providing a selective advantages
- increased cell proliferation or drug resistance, the mutation will be selected for.
how mutations arise:
- Inherited, present in previous generations or parental germline.
- Spontaneous errors in DNA replication, chromosomal instability.
- Induced e.g. exposures to UV light, tobacco smoke, radiation.
- associated with familial history of cancers.
- BRCA1 mutation in breast and ovarian cancer.
- Lynch syndrome in colorectal cancers.
- those with relatives diagnosed with chronic lymphocyte leukaemia have a 7 fold increased risk to developing the disease
Spontaneous mutations - DNA replication is amazingly accurate. even 99.9999% - efficiency would introduce 1 error per 1 million bases.
- human genome is 3 billion BP long, will give way to 3000 mutation per cell division. - DNA replication introduces one mutation per 100,000,000 bases.
- results in 30 per a cell division.
- DNA repair will correct 99% of these.
- Genetic aberrations can also arise via chromosomal instability.
- Gain or loss of whole/part of chromosomes e.g. leading to amplification of HER2 in breast cancer. - Aneuploidy (change in chromosome number) is a frequent feature of tumours
Do all mutation lead to cancer
changes in DNA does not always lead to changes in proteins.does the mutation occur within gene?
amino acid sequence?
- if so, within an exon or intron?
- only 1.25% of the genome codes for protein.
- if within an exon, does the base change affect the
- Redundancy: more than one codon per amino acid ( 64 codons for 20 amino acids)
- environmental exposures.
- UV lights induces the formation of thymine dimers.
- Dimers affect replication and transcription. Normally repaired by nucleotide excision repair.
Types of mutations: - Point mutations - single base changes in DNA sequence., Indels and chromosomal changes.
The genetic change can be referred to as transition or transversion. Transition is the result of the base still being purine or still being pyrimidine. ( e.g. G to A or C to T. ) Transversions results in a change from purine to pyrimidine or from pyrimidine to purine ( T to G) Pyrimidines have a y in them: cytosine and thymine
Point mutations are single base changes in DNA sequence. they can be categorized according to their affect.
Synonymous results in no change in amino acid sequence.
Nonsynonymous / missense – results in a different amino acid.
Nonsense results in a stop codon being prematurely introduced.
Frameshift insertion or deletion results in changes in reading frame.
Indel refer to insertion or deletion of bases in the genome.
these can vary in size from 1bp to 10kb
similar to point mutation they can lead to frameshift unless divisible by 3
inherited defects such a BRCA 1 are indels.
Gain or loss of whole chromosomes (aneuploidy)
Amplifications and deletions
translocations between chromosomes.
In leukaemia large-scale chromosomal changes are common.
e.g. is the Philadelphia chromosome in chronic myeloid leukaemia.
Produces the BCR-ABL fusion gene.
ABL is a tyrosine kinase involved in cell proliferation and differentiation. .
ABL becomes constitutively active(loses regular domain following the translocation)responsible for driving the growth of malignant cells.
Frequency by mutation type.
Chromosomal changes are frequent
drivers of leukaemia.
most changes in solid tumours are smaller, with point mutations being the most dominant genetic change.
most indels are very small (10bp)
Forms of cancer.
- originates from epithelial cells; most common form.
- originates in bone and soft tissue e.g. muscles and fibrous tissue.
- which is cancers of the white blood cell that do not form solid tumours.
- malignancy of lymphocytes, in lymph nodes.
- disease originates from melanocytes.
- Cancer incidence shows variation by country.
- Differences in genetics.
- Differences screening and diagnostics.
- differences in exposures.
- Incidence of cancer usually increases with age.
- increases sharply from the age of 55.
the rate declines at the age of 90.