Structural variant based MRD testing is coming to an oncologist near you

Minimal Residual Disease (the “M” can also stand for “Molecular” or “Measurable”) is a term used to describe the trace amount of cancer left in a patient’s body after treatment.

This is typically detected by tracking cancer specific biomarkers in blood over time to determine if or when a cancer recurs.

These tests are usually referred to as liquid biopsies!

But, back in the day, MRD tests were based on markers known to be common to specific cancer types.

Unfortunately, these early tests had limited value because cancer is cancer and not all of them behave predictably.

They’re all a little different!

They all contain mutations that are unique to them, and so if you’re not developing a test that’s specific to them, there’s a chance you might miss them if they do start to come back!

Thankfully, there are a couple ways around this problem.

One is to do very deep sequencing of blood every couple of months to find variants that appear to be related to a cancer, but doing a lot of deep whole genome sequencing can get pretty expensive!

That’s why a good number of MRD tests use a “tumor informed” approach where they sequence the tumor to find all of the variants in a sample and then pick a handful of those to create a “fingerprint” to track over time.

Creating a fingerprint of the tumor reduces cost and complexity while increasing sensitivity because now you actually know what you’re looking for!

But cancers can have a lot of different types of variants so it’s important to pick ones that you think happened early in development (because they’re probably really important for cancer survival!) and pick variants you can detect with high confidence.

For the longest time, the variants that were used in MRD were single nucleotide variants (SNVs).

Mostly because high throughput sequencers are really good at detecting these, but we know that other types of variants, like structural variants (SVs - where big chunks of the genome have rearranged themselves), are just as important in cancer!

In the figure above, you can see that all of the major cancer types contain SVs and the nice thing about SVs is that there’s evidence that they’re some of the earliest mutations to develop during oncogenesis (when normal cells turn into cancer cells).

This means that they’re also probably going to stick around and not get lost as a tumor evolves.

But SVs also offer another important advantage:

They’re REALLY easy to detect using PCR!

And using PCR for MRD detection has distinct advantages over sequencing because it’s a much faster process but also, since it has a lower background, PCR can be 2-3 log more sensitive than sequencing.

What that means for patients is that we can catch recurrences sooner, reduce false negatives, and intervene before symptoms return or cancer spreads again!

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Disclosure: I am the VP of Technology Development at SAGA Diagnostics - a company that uses SVs in MRD testing