Biomarker panel and methods for detecting microsatellite instability in cancers

Abstract

The present invention generally relates to the field of cancer, in particular to cancers having microsatellite instability (MSI) and / or mismatch repair (MMR-) deficiency. Examples of such cancers include many colorectal, gastric, and endometrial tumors. Accordingly, the present invention provides a novel diagnostic marker panel for analyzing MSI loci, together with methods and kits of using said panel in the detection of cancers having microsatellite instability (MSI) and / or mismatch repair (MMR-) deficiency.

Description

technical field [0001] The present invention relates generally to the field of cancer, and in particular to cancers with microsatellite instability (MSI) and / or mismatch repair (MMR-) deficiencies. Examples of such cancers include many colorectal, gastric and endometrial tumors. Accordingly, the present invention provides novel diagnostic marker panels for the analysis of the MSI locus, as well as methods of using said panels for the detection of cancers with microsatellite instability (MSI) and / or mismatch repair (MMR-) deficiency. Methods and kits. Background technique [0002] In Europe and the United States, approximately 440,000 patients are diagnosed with colorectal cancer (CRC) each year. Recent guidelines, such as NCCN Guidelines for Patients: Colon Cancer Version 1.2017 and ESMO Clinical Practice Guidelines on familial risk-colorectal cancer, recommend tumor testing for DNA mismatch repair (MMR) deficiency and / or MSI status in all CRC patients. However, these tes...

AI Technical Summary

Problems solved by technology

With respect to (ii), however, high-resolution melting curve analysis of dsDNA-intercalating dyes has very limited multiplexability to screen for several different MSI markers in a single run, since the melting temperatures of each marker amplicon need to be sufficiently different to no overlapping signals

Furthermore, since this strategy relies on heteroduplex formation between normal and mutant length alleles, it is also less sensitive than other alternatives

Next, regarding (iii), mass spectrometry-based methods (Zhao et al., 2014) are in principle also suitable for automation, but require specialized instruments and highly skilled personnel for data interpretation

Finally, with respect to (iv), NGS certainly has the advantage of looking at a large number of MSI-indicated locations in the genome or exome, not just selectable markers, and although this approach is also in principle at least partially automated, it is currently very Expensive and requires dedicated NGS hardware

Regarding homopolymer scoring, NGS is still insufficient for repeat scoring of individual homopolymer repeats, as it is still prone to losing information about single nucleotide indels in a string of repeat nucleotides

Also, it is still time consuming, complex and requires trained analysts due to the large amount of data generated

[0012] In conclusion, MSI testing represents a high medical need that is only partially met by existing diagnostic methods due to their technical limitations

Importantly, these include limited detection capabilities, high costs and / or turnaround times, requirements for specialized equipment and / or interpretation by trained experts

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