Cancer Genomes Flashcards
Define passenger and driver mutations
Somatic mutations
Driver mutations: pathogenic variants in key cancer genes likely to be causing oncogenesis.
Passenger mutations: variants in non relevant genes or benign variants in cancer genes. Not likely to be involved in the process of oncogenesis.
However, it can cause high mutational burden which leads to a more unstable mutagenic phenotype
What is the tumour mutational burden and mutational signature?
Tumour mutational burden
The number of somatically acquired mutations present in cancer DNA
Mutational signature
A pattern of mutation types which can give clues to the underlying mutagenic processes at work in the cancer cells
How would you identify somatic tumour specific mutations?
Need to sequence two whole genomes: the germline genome and the tumour genome. The tumour information is presented as a Circos plot.
Genetic variation which is present in the whole genome sequencing of the tumour but NOT the germline is considered somatically acquired
How would the type of tumour influence the type of sample you take to identify somatic vs germline mutations?
For solid tumours germline = lymphocytic DNA (blood sample)
For haematological malignancies the tumour sample is from blood and germline will be another tissue – for example fibrocytic DNA from a skin biopsy
For what types of cancer is whole genome sequencing available?
We can identify driver mutations through single mutation testing, gene panels and whole genome sequencing
Whole genome sequencing is only available for:
Childhood cancer
Haematological malignancies
Certain metastatic cancers
Give Driver mutation and pathway examples
BRAF V600E is an oncogene
This specific aa change at position 600 causes over activation of RAS-MAPK pathway. A key driver mutation in melanoma and colorectal cancer
Rb1 is a tumour suppressor gene. Controls cell cycle, prevents activation of replication
BRCA1 or BRCA2 is a Tumour suppressor gene/DNA repair gene.
Failure of homologous recombination
MLH1 is a Tumour suppressor gene/DNA repair gene
Can have methylation of MHL1’s promotor region which suppresses it (an oncogenic mechanism)
What can cause oncogenesis in oncogenes vs tumour suppressor genes?
All a tumour suppressor genes need to have loss of both copies of the gene in the tumour in order for oncogenesis.
In oncogenes like BRAF you only need a single driver mutation to get oncogenesis.
What happens if we don’t find a driver mutation?
We don’t always find a driver mutation.
Maybe bc we don’t know the driver mutations for every cancer type
Cancer genomes can have huge numbers of mutations
We can look at other information from the cancer genome to help guide management
What happens if we only do driver mutation testing without paired whole genome sequencing?
If we undertake paired whole genome sequencing we know if a variant seen somatically is also in the germline
If we only undertake driver mutation testing or large panel sequencing without paired germline we do not know if a variant is somatic only or may also be present in the germline
Driver mutations found somatically may indicate a need for germline testing to exclude/confirm an inherited cancer predisposition. In which circumstances does this happen?
If we suspect a Class 4/5 variant in a known cancer susceptibility gene
Variant Allele Frequency >30%
Need to consider difference between on-tumour and off-tumour findings
Use this graph to explain the tumour mutational burden
Each dot= sequencing of a tumour DNA from a group of patients.
It tells us the number of non synonymous variants per mb of exon in each of those tumours. Different cancers have diff ranges.
The red line across the middle gives you the average number per tumour type of those mutations. Eg endometrial carcinoma has a huge range.
Dots at the top= v high mutational burden cell which is v diff. It avoids detection by our immune cells bc a PDL protein ‘hides’ the cancer cell.
Describe cancer immunotherapy
PDL1 hides the cancer cell from immune system detection. Immunotherapies remove the cancer cell’s ability to hide itself using PDL1. T cells can thus recognise the cancer cells again and kill them.
Immunotherapy agents 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 w mismatch repair deficiency or proof-reading polymerase deficiency
What is mutational profiling?
•Each of our cells is subject to multiple mutagenic processes. The exposure to a mutagenic process can be of differing lengths
•Each cell will contain a “pattern” of mutations which reflect the:
Type of mutagenic process
Length of the exposure to the mutagenic process
Eg being a smoker for 10 yrs has a diff profile to constant UV exposure
We can use mutational profiling to identify any common “mutational signatures”
What is this and what does it represent?
This is a mutational profile of 21 breast cancer types. The 6 heat maps represent the 6 dif base substitutions that can occur and how many times they occur within a specific codon.
The obvious feature= red stripe down the middle. This tells us it is v common for a C to mutate to a T when it is followed by a G.
It’s hard to find differences by eye, so a computer does this for you by non-negative matrix factorisation (pulling out specific patterns)
Give an example of a mutational signature
- The major mutation type is C>T base substitution (C mutating into a T). This is a signature 7 mutation
- The highest number of C>T mutations occur in the sequence is where a “T” is immediately 5’ prime (preceeding) the mutated “C”
- The C>T mutation also occurs where a “C” is immediately 5’ to the mutated “C”
What is the significance of finding a BRCA mutation? .
Finding an underlying BRCA mutation will change treatment and management options:
