Mismatch Repair Deficiency and Microsatellite Instability

Abstract

Mismatch repair deficiency (MMRd) is caused by the biallelic inactivation of an MMR gene, which can be attributed either to an inherited or an acquired pathway. MMRd is characterized by the inability of cells to repair spontaneous mutations in microsatellites that occur during replication. Microsatellites are repetitive nucleotide sequences composed of one to six base pairs. Mutations in microsatellites lead to deletions or insertions of sequence units that are designated as microsatellite instability (MSI). MMRd is diagnosed by immunochemistry and is characterized by loss of nuclear immunostaining for at least one of the four MMR proteins that are routinely examined, i.e., MSH2, MSH6, MLH1 and PMS2. Available tests for MSI are PCR and next generation sequencing. MMRd and MSI predispose to tumor initiation and progression, increase tumor mutational burden as well as tumor immunogenicity, facilitate the activation of the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) immune checkpoint pathway and serve as prognostic and predictive biomarkers in solid tumors.

Testing deficient mismatch repair and microsatellite instability

“…In den meisten Fällen (70–80 %) ist MLH1 aufgrund einer mit dem Alter zunehmenden Methylierung Cytidin-reicher Promotorabschnitte betroffen (erworbene Form). Ferner treten pathogene MMR-Genmutationen auf, die meist über die Keimbahn vererbt werden (hereditäre/konstitutionelle Form) und seltener auch somatisch erworben werden können (Review in Schöniger, Rüschoff [ 25 ]).…”

Implementing an On-Slide Molecular Classification of Gastric Cancer: A Tissue Microarray Study

“…In our diagnostic routine, we assess MMR status using all four IHC markers; however, for this work, we used only two of the biomarkers (MLH1 and MSH2), principally in order to save tissue sections. Since MLH1 promoter methylation and germline mutation in MLH1 and MSH2 are the most frequent causes of MMR deficiency in gastric cancer, some institutes use only MLH1 and MSH2 in the diagnostic routine [ 43 ]. In our experience, the use of all four markers aids interpretation, and we would not advocate implementing GC classification using only two of these biomarkers.…”

The PD-1/PD-L1 Pathway: A Perspective on Comparative Immuno-Oncology

“…Within tumor tissue, these antibodies prevent the binding between PD-L1 of tumor cells and PD-1 of lymphocytes and thereby restore the anti-cancer immune responses [ 12 ], whereby the cytolysis of tumor cells is mainly mediated by CD8+ cyTCs [ 12 ]. To determine the eligibility of a patient for immune checkpoint therapy, the presence of PD-L1-positive tumor cells and/or immune cells is analyzed [ 24 ] or the presence of dMMR or MSI-H is determined [ 43 , 44 , 82 ]. It was noted, however, that not all tumors fulfilling these criteria show long-term remission after immune checkpoint therapy [ 24 ].…”

“…The high immunogenicity of “hot tumors” can be caused by different molecular mechanisms. For example, it may be associated with mismatch repair deficiency (dMMR) and/or high microsatellite instability (MSI-H) [ 43 , 44 , 45 ] or a major histocompatibility complex class II (MHCII) signature [ 46 , 47 ]. Thus, dMMR/MSI-H [ 43 , 44 , 45 ] or MHII signature [ 46 , 47 ] serve as independent and robust biomarkers for predicting a favorable immune response to immune checkpoint inhibition.…”