Somatic genomic tests continued

In the previous step, we identified some sequencing-based tests that are particularly important to know about. Now, let’s look at some that don’t use sequencing.

Fluorescence in situ hybridization (FISH)

_{Figure 1: Non-small cell lung cancer tissue with chromosomes stained to assess CCDC6 gene (green probe) and RET gene (red probe) location and position. Image A shows equal amounts of each probe (green and red). Image B shows more red than green probes (see arrow), indicating that there has been an increase in copy number of the RET gene, resulting in increased expression of the gene.}

Molecular tumour profiling

Homologous recombination deficiency (HRD) test

Immunohistochemistry (IHC)

Microsatellite instability analysis (MSI)

Another technique to identify MMR deficiency is microsatellite analysis. Microsatellites are short, repeating sections of DNA, which can expand and vary in length. In MMR deficiency, errors in DNA base pairing are not routinely corrected and can lead to this variation in the number of repeats occurring within the cell, known as microsatellite instability.

MSI testing is used to examine the repeat sizes of select microsatellite markers using massively parallel sequencing technologies. Tumours may be identified as MSI high, indicating instability across multiple markers, or MSI low, indicating instability at one marker only. More commonly, you may hear the term MSI-S, which stands for MSI stable and is often used interchangeably with MSI-L. An MSI-H result is important as it is the molecular fingerprint of an MMR-deficient tumour.

Testing MMR-deficient tumours

There is international data which suggests that immunotherapy may be of benefit in a tumour-agnostic fashion in MMR-deficient tumours. However, in clinical practice, which tumours would be tested and subsequently treated with immunotherapy will also depend on other factors, such as regulatory approvals and national guidelines. When an MMR-deficient tumour is identified, a family history should be taken, and constitutional MMR gene testing should be considered to identify potential Lynch syndrome. This depends on the pattern of loss and results of any additional somatic testing required.

What have we learned?

In summary, the most appropriate test for a cancer patient will depend on the cancer type, the type of variants known to cause oncogenesis in that tumour type, and the most efficient way of detecting this, and the clinical information we wish to identify, whether that is related to diagnosis, prognosis, or therapeutic intent. These steps haven’t covered all possible tumour tests relevant for clinical management. Additional tests include MLH1 promoter hypermethylation, microarray and multiplex ligation-dependent probe amplification (MLPA). You can find out more about these on the GeNotes Knowledge Hub.

The National Genomic Test Directory for cancer will enable you to identify the different tests which are available for each cancer type, as well as the technologies used to identify the relevant underlying genomic variation or molecular mechanism. We’ll be learning more about the test directory later this week, including how to navigate it.

Remember, your local laboratory can also support you in choosing the right test for your patient, so reach out to them if you need support.

Talking point

• Have you ever encountered a situation in which you had to weigh the advantages and disadvantages of different somatic genomic tests when requesting one for a patient? What helped you to decide?