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The value of microsatellite instability testing – now and in the future

Microsatellite instability (MSI) testing of tumour tissue is routinely performed to identify genomic instability (deficiency in one or more DNA mismatch repair (MMR) proteins). MSI status is associated with several diseases, including colon and gastric cancers. Here, we explore the importance of MSI testing, its indications and how liquid biopsy could help with detection.

What is microsatellite instability?

Microsatellites are short-tandem repeated DNA sequences, typically mono- or di-nucleotide repeats. These regions are often prone to replication errors, which can be fixed via the DNA mismatch repair system. However, mismatch repair deficiency (dMMR) can result in the accumulation of mutations in the microsatellite repeat regions. This is known as microsatellite instability or MSI.

Why is MSI testing important?

The presence of MSI provides phenotypic evidence that MMR is not functioning normally. There are two main indications for MSI testing. The classic indication is for Lynch syndrome, a dominant hereditary condition caused by germline mutations in MMR genes MSH2, MLH1, MSH6 or PMS2. These mutations increase the risk of cancers, such as colorectal and endometrial. Around 3-5% of all colorectal and endometrial cancers can be attributed to Lynch syndrome. Additionally, around 15% of sporadic colorectal cancers and 20-30% of sporadic endometrial cancers are MSI-H (MSI-High). These cases are not caused by germline mutations, rather the inactivation of MLH1 via promoter methylation. The second indication for MSI testing is to guide cancer therapy as MSI-H tumour status can be predictive of a positive response to immune checkpoint inhibitor (ICI) therapy in several types of solid tumours.

The MSI analysis workflow is simple. It includes isolation of the DNA from normal and tumour FFPE tissue samples, amplification of the microsatellite repeats via multiplex PCR, fragment separation by capillary electrophoresis and then data analysis to identify differences between normal and tumour samples.

The future for MSI testing and a role for liquid biopsy?

The analysis of tumour-derived ctDNA present in the blood samples – also known as liquid biopsy – is beginning to transform cancer diagnosis. Preliminary data from Dr Pam Ward at USC, indicates that MSI analysis of liquid biopsies from patients may be able to provide both an initial diagnosis but then subsequently could be used to measure the efficacy of treatment. This is particularly important for targeted immune checkpoint inhibitor therapy. Liquid biopsy provides a non-invasive alternative to tissue biopsy when the traditional methods cannot be applied or are too invasive to be used repeatedly. Most importantly, it has the potential to be used to follow up patient response to treatment and potentially pick up abnormalities early (in the case of relapse) so that treatment regimes can then be employed in a timely fashion.

In our recent webinar, Dr Phil Hargreaves, Head of Strategic Marketing & Business Development, Promega, commented:

“I think what is particularly exciting is the potential for liquid biopsy as a route to detect MSI status in circulating tumour DNA and then to track the response to anti-PD1 therapy, so that means the patient does not have to have repeated invasive biopsies.”

Image credit: By kjpargeter –

More on these topics

Genetics / Liquid Biopsy / MSI