|
Pearl
Not all genetic mutations are created equal
Understanding the genetic drivers of cancers have led to an explosion of new targeted therapies since the initial approval of imatinib in 2001 for CML (and most recently with revumenib approved last week for acute leukemia with a KMT2A translocation)
Let’s talk about some of these changes we see
Point Mutations
There are different types of point mutations:
- Single nucleotide change, like KRAS mutations
- Silent mutations which is when there is no change in amino acid. For example, AAA mutating to AAG is a silent mutation because both code for lysine so the end result is the same.
- Missense mutations mean that a different amino acid is substituted. Some (not all) BRCA mutations are these.
- Nonsense mutations are stop signals leading to an unfinished protein. This is visualized with the use of the asterisk symbol. An example of this is a mutation in the TP53 tumor suppressor gene.
Frameshift mutations
This is when base pairs are added or deleted but not in groups of 3 which alters how the code is read
For example, consider this sentence a DNA sequence:
Bob hit the bat
The code is read in groups of 3, so if the ‘it’ were deleted, it would be read as:
Bob hth eba t 🤔
That doesn’t make sense to read and wouldn’t make sense to build a protein
An example of a frameshift mutation is the genetic cause of cystic fibrosis
Splice site mutations
This is when a change happens at the boundary of an exon and the splice site (called an intron - a non-coding section) which can lead to deletion of exons or inclusion of introns
An example is the MET exon 14 skip mutation in lung cancer where the exon 14 section of the MET gene is skipped during replication
Rearrangements
These happen when parts of the chromosome are moved from one to another
The most well known example is t(9,22) [this is read out loud as translocation 9,22], which means sections of chromosomes 9 and 22 swap places which produces the BCR-ABL protein and CML (chronic myeloid leukemia)
Gene fusions
These happen when 2 genes are pushed together
An example of this is the EMLA4-ALK fusion in lung cancer. There are at least 15 different variations of this fusion protein and they can respond differently to our ALK inhibitors so the presence of this doesn’t guarantee response to those drugs unfortunately.
What’s cool is that when you know this information, you can get more detail from genetic reports
Here are a few examples of what you might see:
Tp53r213q
The first section tells you what gene you’re looking at - here it’s the tp53 gene. The next section is telling you that there should be an r at the 213 spot in the sequence but there is a q instead.
Chek2q51*
In the Chek2 gene there is a stop codon (because it has *) at location 51 which means it’s been truncated (or cut off)
It’s important to remember, a mutation alone isn’t the issue
The issue is when that mutation causes a problem with the protein it codes for (a pathogenic mutation) and if that mutated protein leads to cancer (oncogenic mutation).
A great resource for genetics in oncology is OncoKB, a database developed at Memorial Sloan Kettering (there is a quick overview video on their about page if you want context on it) |
