Cancer genomics 2: Genome in Cancer care Flashcards
Why do cancer patients have 2 genomes?
- They have their germline/constitutional genome (genetic code we’re born with, present in all of our cells, including germline)
- They also have their somatic/tumour genome (genetic code of the cancer cell, not present in germline cells)
For this reason, germline variants can be passed onto offspring, but not somatic variants
Define cancer genome
Genetic code of the cancer cell(s)
Describe the circos plot as a diagram of the cancer genome
Has 6 layers: From outer to inner
- Depth of coverage - Shows how deep the sequencing of the tumour has gone
- Copy number changed
- Red = Deletion
- Yellow = Loss of heterozygosity
- Green = Duplication
- Somatic indels - Insertion of bases
- Somatic SNVs (Single Nucleotide Variants)
- 23 pairs of chromosomes in body
- Structural rearrangements, show as lines within centre of circos plot, looks like a web
- Purple = Inversion
- Green = Translocation
Define mutational signature
Pattern of mutation types which can give clues to the underlying mutagenic processes at work in the cancer cells, why the cancer developed in the first place
‘Molecular footprint’ of a tumour
Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which geneates a characteristic mutational signature
What caused the pattern of mutations in the cell (mutational signatures)
Define mutational burden
The number of somatically acquired mutations present in cancer DNA
This can indicate failure of a DNA repair pathway. Could indicate that immunotherapy may induce a clinical response in a tumour ganostic manner.
Pan-genomic markers important for treatment - Tumour mutational burden (TMB)
Define passenger mutations
- Don’t in theory contribute to oncogenesis
- High mutational burden may lead to a more unstable mutagenic phenotype, this happens when there’s an accumulation of passenger mutations
- Sometimes can be hard to tell if variant in cancer gene is a driver mutation or a benign variant not impacting on function of gene
Define driver mutations
Changes in DNA sequence of genes that cause cells to become cancer cells and grow and spread in the body
They can affect:
- Oncogenes - Genes that have mutated to drive and support the development of certain cancers
- Tumour suppressor genes - Normal genes that slow down cell division or promote apoptosis
- DNA repair genes/mechanisms - These mechanisms either direct reversal of the chemical reaction responsible for damaging DNA or removal damaged bases followed by their replacement with newly synthesised DNA. Damage to DNA repair genes impairs the ability of DNA to repair itself, increasing the risk of developing cancer
What is the function of SNP genotyping?
Identify the nucleotide present at a specific genome location, so basically SNP genotyping determines the state of only a targeted set of genetic sites within the genome
What is the function of DNA sequencing (NGS)?
Identify all the nucleotides present in a section of DNA
DNA sequencing is the process of determining the exact order of the 4 bases in a specific section of DNA
DNA sequencing can identify high penetrance variants that can increase lifetime likelihood of developing cancer, this is what it can be used for
What is the function of array CGH?
Identify gains and losses or rearrangements of chromosomes
Compares DNA to reference sample, allowing for detection of chromosome imbalances that are too small to be detected by looking down a microscope (microdeletions or microduplications)
How can we test for somatic mutations?
- Single driver mutations
- Gene panels
- Whole genome sequencing
- Childhood cancer
- Haematological malignancies
- Certain metastatic cancers
Describe the use of targeted therapy
- Identify the genetic changes in the cancer driving the cancer
- Target those with a specific therapy
- BRAF mutations in melanoma treated with BRAF inhibitors
Why might whole exome/ genome sequencing be used for cancer genes?
When gene panels/single gene testing do not provide answers, whole exome or genome sequencing can provide answers
- Reading the cancer genome can tell:
- What the important ‘driver’ mutations are causing oncogenesis
- What caused the pattern of mutations in the cell (mutational signatures)
- Cigarette smoke
- UV light
- Defects in DNA repair genes
- Pan-genomic markers important for treatment - Tumour mutational burden (TMB)
- Can also monitor changes in cancer cells with treatment
Describe tumour mutational burden and therapy
- Immunotherapy agents have been shown to have clinical efficacy in tumours with a high mutational burden
- A high mutational burden can be caused by failure of DNA repair pathways and often occurs with mismatch repair deficiency of proof-reading polymerase deficiency
- Example: Pembroluzimab in colorectal cancer with high tumour mutational burden
What are the different ways genetics can increase susceptibility to cancer?
- Multiple low risk genetic changes adding up - Polygenic risk
- A single high/moderate risk genetic change - Cancer susceptibility genes
Describe DNA mutagens that can lead to cancer
- Internal:
- ROS
- Ineffective DNA repair mechanisms
- External:
- UV light, ionising radiation
- Cigarette smoke, chemical consumption
Describe mutational profiling
- Each of our cells is subject to multiple mutagenic processes
- Exposure to a mutagenic process can be of differing lengths
- Each cell will conain a ‘pattern’ of mutations which reflect:
- Mutagenic process
- Length of exposure to mutagenic process
Describe the BRAF V600E mutation
- Oncogene
- Over activation of RAS-MAPK pathway
Describe the Rb1 mutation
- Tumour suppressor gene
- Control of cell cycle, prevents activation of replication
Describe BRCA 1/ BRCA 2 mutation
- Tumour suppresor gene/DNA repair gene
- Failure of homologous recombination
Describe MLH1 mutation
- Tumour suppressor gene/DNA repair gene
- Can have epigenetic suppression: methylation of promotor region
- Failure of mismatch repair
How can genomics be used to guide cancer patients’ treatments?
We can read the genetic information about their cancer (cancer genome):
- Can guide treatment options
- Personalised therapies
- Monitoring of relapse/treatment
We can read the genetic information they were born with (somatic genome):
- Lookf for genetic factors influencing cancer risk
- Information about future cancer risk
- Information for relatives
- Screening, prevention, early detection
What is polygenic risk?
Multiple low risk genetic changes, adding up together
Define cancer susceptibility genes
A single high/moderate risk genetic change
What is meant when a disease is described as monogenic?
Diseases in which the disease state in a family is determined by a single gene mutation
