Cancer is a genetic disease. In consequence, we are interested in surveying the genomes of tumor cells to find out the specific alterations that unregulated them. Some of these alterations will give the tumor a selective growth advantage (driver alterations). Tumor cells accumulate a bigger number of alterations that are biologically inert (passengers). We consider three types of alterations:
Next generation sequencing technologies are the de facto standard in studying genetic alterations in tumors. The process is as follows:
Usually, we need to make some cancer-specific considerations, which might hinder the ability to detect mutations:
Trade-off between specificity and sensitivity. We will choose a balance depending on our goals. Different callers give different trade-offs, and we need to understand our tool of choice.
Mut signs. Characteristic patters of somatic…. We use passenger mutations to get them.
With every cell division, there will be a probability of error naturally. More errors will happen due to exposure to mutagens. A failing error-correcting mechanism is also a posibility. We can caracterize each patient as a combination of the sigmatures.
Non-negative matrix factorization (NMF): developed to find features in photography. Different features from DNA plots to get differemt mutational signatures.
Some of the signatures, we can link to something. For example smokers have a very particular mutational signature. Its the case for sun-exposure too.
Deletions at repeats: tend to be short. Deletions at microhomology: tend to be larger.
Structural rearrangenent signatures: we can characterize them according to clustered in specific genomic regions and others non-clustered. We can also look at the size. Then perform NMF.
Breakage-fusion-bridge mechanism (BFB): there is a breakage in the chromosome, and a telomere is lost. There is a fusion with another chromosome. During anaphase, opposite centromeres are pulled from different ends, and a new breakage, now mechanical, happens. And this happens again and again, with the chromosome growing in size. This will leave several footprints: only some number of repetitions are possible, we will observe foldback inversion, and it will lead to abnormal read pairs. All in all, we can detect situations compatible with the BRB compatible.
Scatter the chromosomes and rearrange randomly.