Abstract
Immune-checkpoint inhibitors (ICIs) play a key role in the treatment of advanced stage colorectal cancer (CRC) patients featuring a deficient DNA mismatch repair (dMMR) system or a high microsatellite instability (MSI-H) profile. However, beyond the established role in CRC patients, ICIs have highly proven efficacy in other solid tumors featuring MSI-H/dMMR status represented by endometrial, gastric, ovarian, prostatic, and pancreatic carcinomas (EC, GC, OC, PrC, and PaC). Our aim was to compare the concordance rates among the Idylla™ MSI test, TapeStation 4200, and immunohistochemical (IHC) analysis in assessing MSI-H/dMMR status in EC, GC, OC, PrC, and PaC patients. The Sanger sequencing-based Titano MSI test was used in discordant cases. One hundred and eighty-five cases (n = 40 PrC, n = 39 GC, n = 38 OC, n = 35 PaC, and n = 33 EC) were retrospectively selected. MMR protein expression was evaluated by IHC. After DNA quality and quantity evaluations, the IdyllaTM and TapeStation 4200 platforms were adopted for the evaluation of MSI status. Remarkably, compared to IHC, the Idylla™ platform achieved a global concordance rate of 94.5% (154/163) for the microsatellite stable (MSS)/proficient MMR (pMMR) cases and 77.3% (17/22) for the MSI-H/dMMR cases. Similarly, a global concordance rate of 91.4% (149/163) and 68.2% (15/22) for MSS/pMMR and MSI-H/dMMR cases was also identified between IHC and the TapeStation 4200 microfluidic system. In addition, a global concordance of 93.1% (148/159) and 69.2% (18/26) for MSS/pMMR and MSI-H/dMMR cases was observed between the Idylla™ and TapeStation 4200 platforms. Discordant cases were analyzed using the Titano MSI kit. Overall, our data pinpointed a central role for molecular techniques in the diagnostic evaluation of dMMR/MSI-H status not only in CRC patients but also in other types of solid tumors.
Highlights
DNA mismatch repair (MMR) is a highly conserved system responsible for restoring mismatching errors, such as single base mismatches, or small insertions and deletions.When these errors are not corrected, owing to a flawed MMR system, genomic steadiness is disrupted during DNA replication and recombination—a phenomenon that eventually gives rise to multiple cancer-associated mutations [1,2,3,4,5]
A total of four 5-micron thick slides obtained from tumor specimens were used for microsatellite instability (MSI) analysis, according to the manufacturer’s instructions
A high concordance rate was observed between the IdyllaTM platform and IHC (94.5% and 77.3% for the for microsatellite stable (MSS)/proficient MMR (pMMR) and MSI-H/DNA mismatch repair (dMMR) cases, respectively), and between the TapeStation 4200 microfluidic system and IHC (91.4% and 68.2% for the MSS/pMMR and MSI-H/dMMR cases, respectively)
Summary
DNA mismatch repair (MMR) is a highly conserved system responsible for restoring mismatching errors, such as single base mismatches, or small insertions and deletions When these errors are not corrected, owing to a flawed MMR system, genomic steadiness is disrupted during DNA replication and recombination—a phenomenon that eventually gives rise to multiple cancer-associated mutations [1,2,3,4,5]. Evaluation and interpretation of immunohistochemical results may at times be challenging because of intra- and inter-observer variability and pre-analytical and analytical issues [1] In this scenario, evaluation of microsatellite instability (MSI) through molecular approaches, such as polymerase chain reaction (PCR), genomic sequencing, and capillary electrophoresis, has been proposed as a valuable alternative to overcome some of the issues inherent to immunohistochemistry (IHC) [1,11]
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