Cancer Genomics - Cancer as a genetic disease - week 10 Flashcards
cancer considered to be a
genetic disease
Genetic alterations in cancer
• Non-lethal genetic change lies at the cancer development
o As a result of Spontaneous error occurring in somatic DNA
o As a result of Environment exposure to exogenous agents (i.e. virsuses or specific chemicals) or to endogenous products of cellular metabolism or as a result of inherited or germline mutations
Clonal expansion
tumour is formed by clonal expansion of single precursor cell, this is achieved as when DNA damage has occurred in a cell this change is passed on to all daughter cells
Genetic alterations that initiate cancer development known as initiator mutations occur in regulatory genes, such as:
o Oncogenes (growth promoting genes) o Tumour suppressors (include growth inhibiting genes, classic tumour suppressor genes, and apoptosis and DNA repair genes)
Stepwise accumulation of complementary mutations –
o After initiator mutation for cancer to develop there has to be other mutations, and these mutations occur in a stepwise fashion over time allowing the cell to develop several properties enabling them to become fully malignant or cancerous - these properties are known as the Hallmarks of Cancer.
Driver and passenger mutations
- Can see the stepwise progression from a normal cell through to a genetically heterogeneous cancer
- in addition to the initiator mutation which starts progression of carcinogenesis there are also driver and passenger mutations which occur
• Passenger mutations –
genetic changes that occur within tumours that have no phenotypic consequence so they do not change the property of the cells they occur in
• Driver mutations –
mutations that the cells acquire in addition to the initiator mutation that contribute to the development of cancer
Knowing the initiator and driver mutations in a particular cancer allows
targeted therapies to be developed and used to treat these cancers.
- Genomic evolution of a cancer cell
from fertilisation onwards
the genome acquires passenger mutations that don’t affect phenotype of cells they occur in
- Genomic evolution of a cancer cell
Later in life,
by chance a mutation occurs in the regulatory genes of 1 cell that initiates cancer development
- Genomic evolution of a cancer cell,
clonal expansion of this 1 cell,
leads to the formation of a benign tumour and then later the acquisition of other driver mutations and clonal expansion of these cells within the benign tumour leads to increasingly a more invasive cancer which ultimately becomes resistance to chemotherapy as result of acquiring particular driver mutations
- Genomic evolution of a cancer cell,
one key step
in the development of a fully malignant tumour is the development of the mutator phenotype.
- Genomic evolution of a cancer cell,
DNA repair gene…
If a DNA repair gene becomes mutated, it impairs the ability of the cell to recognise and repair non-lethal genetic changes so cells acquire mutations at a faster rate than usual increasing likelihood that regulator genes become mutated which is known as genomic instability.
Survival of the fittest - fully malignant cancers are
not homogeneous
tumours initially
1 identical subtype of cell. o The tumour will start from on identical subtype however an established tumour that has come to clinical attention will have undergone at least 30 mitoses (cell doubling).
survival of the fittest - Mutator phenotype means all cells are acquiring
new mutations. Some of these mutations will be lethal to the cell and the cell will apoptose,
others will not have any affect and others will enable the cell to become more aggressive or more malignant.
survival of the fittest - eventually those cells that have acquired these aggressive mutations will
become dominant in the tumour and develop as a subclone until another more aggressive mutation occurs .
o Some cells – apoptosis
o Some cells – new mutations which make them more aggressive
• Explains development of cancer and response to therapy
This survival of the fittest behaviour of cancer cells explains the
development of cancer from the normal cell but also the behaviours of cancer cell while undergoing therapy. Under therapeutic selective pressure, resistance to treatment can emerge as a result of the expansion of pre-existing subclonal populations or from the evolution of drug-tolerant cells
how many genetic changes in a tumour?
fully malignant cancers, as a result genomic instability and clonal expansion, develop many, many mutations.
what type of cancer has the highest number of mutations?
those tumours that are defective in DNA repair have the highest number of mutations *between 500 and 1500) however many of the adult solid tumours that do not have defective DNA repair have 10’s of different changes identified.
what type of cancers have the fewest number of mutations
Paediatric tumour have the fewest changes identified, this is like as a result of these tumour developing early in life so there hasn’t been time for them to acquire so many different changes.
Summary - multiple
Multiple genetic changes in most tumours (especially malignant)
Summary - regulatory genes
If genetic changes occur in specific regulatory genes that affect the cells growth and stability these can change the properties of a cell and are known as intiator and driver mutations. Passenger mutations occur by chance and do not affect the phenotype of the cells.
summary - tumours are clonal
Tumours are clonal in origin but heterogeneous in nature
summary - tumours start
Tumours initially start as a clonal expansion of one cell however as the develops more and more genetic changes some become more aggressive and malignant than others and it is a case of survival of fittest with multiple subclones developing leading to a heterogenous population of cells in on cancer. Knowing the driver mutations of specific cancer is useful when developing new cancer therapies.
Summary - survival of the fittest
Survival of the fittest contributes to development of a malignant tumour and response to therapy
Summary - understanding
Understanding the mutations that drive a tumour is useful when developing targeted cancer therapy
