Overview of a comparative analysis of microsatellite instability and standard mismatch repair protein-deficiency tests in a large cancer cohort.

Mismatch repair deficiency (dMMR) with microsatellite instability (MSI) is frequent in cancer, particularly in gastrointestinal and endometrial malignancies. The increased tumor mutational burden renders dMMR/MSI tumors suitable targets for immune checkpoint inhibitors-provided the regulatory genetic defect can be detected. dMMR and MSI are considered equally effective predictors of the efficacy of ICIs; however, while dMMR testing is based on detection of missing MMR proteins in immunohistochemistry (IHC), MSI polymerase chain reaction (PCR) testing focuses on the consequences of dMMR at the genomic level. A retrospective analysis was carried out in a large cancer cohort (n = 1306). dMMR was tested by four IHC reactions (MLH1, PMS2, MSH2, MSH6), and MSI was assessed by pentaplex PCR (BAT-25, BAT-26, MONO-27, NR-21, NR-24) in 703 cases. In 64 cases (5%), technical failures (mostly poor preanalytical fixation) prevented dMMR/MSI testing. Tumors were colorectal (CRC; n: 978), cancer of unknown primary (n: 126), endometrial (n: 39), pancreatic (n: 36), and gastric (n: 33). dMMR was diagnosed as classical, nonclassical, or unusual, depending on IHC. The MSI-high incidence was 12.1% overall and similar in the CRC subcohort. Interestingly, the dMMR incidence was higher in the total cohort (20.3%) and similar in the CRC subcohort. The incidences of proficient MMR (pMMR) and microsatellite stability (MSS) were similar in the total cohort and in the CRC subcohort. A 19.3% discrepancy was found between MMR IHC and MSI PCR for the entire cohort, independent of tumor types. In the case of pMMR, the discrepancy rate for MSS/MSI-low was low (2.0%; entire cohort and the CRC subcohort). However, the discrepancy between dMMR and MSI-high was high within the entire cohort (60.9%) and in the CRC (58.6%) and non-CRC subcohorts (68%). This high discrepancy was not due to tumors with a low T/N ratio. Regarding dMMR phenotypes, classical dMMR had a ~ 60% correlation with MSI-high status, while non-classical dMMR had a much lower and unusual dMMR a very low (< 10%) correlation with MSI-high in the entire cohort and in the CRC subcohort. Overall, the MSI PCR sensitivity for MMR IHC status was very low. dMMR and MSI-high likely result in an increased rate of structurally altered proteins, i.e., neoantigens, and the efficacy of cancer immunotherapies is thus expected to be higher. We compared MMR IHC to MSI PCR in a large cohort of cancer patients to study how PCR test results correlate to MMR IHC. Our data imply that preanalytical factors strongly influence the results of MMR IHC and MSI PCR and may question the current dogma that dMMR phenotype and genetic MSI status are equivalent predictive markers for immunotherapies.

Kiss A ，Nádorvári ML ，Kulka J ，Barbai T ，Rásó E ，Kenessey I ，Lotz G ，Tímár J ... -  《-》

Microsatellite instability and high tumor mutational burden detected by next generation sequencing are concordant with loss of mismatch repair proteins by immunohistochemistry.

Impairment of DNA mismatch repair function in neoplasms can be assessed by DNA-based methods to assess for high microsatellite instability (MSI-High) or immunohistochemical (IHC) analysis to assess for deficiency of mismatch repair proteins (dMMR). Neoplasms with mismatch repair deficiency often have high tumor mutational burden (TMB-High). MSI-High, dMMR, and TMB-High are all histology agnostic biomarkers for potential therapy using immune checkpoint inhibitors (ICI). In this single center, retrospective study, our primary aim was to assess if NGS-based positive TMB/MSI findings are concordant with patient matched concurrent MMR IHC studies. In addition, we determined if positive TMB/MSI findings are attributable to genetic/epigenetic alterations of MMR genes. Finally, we explored potential associations between IHC, TMB and MSI findings and specific tumor types We screened 4,258 patients in our database who had tumor-normal-testing with our institutional high-throughput NGS-based CLIA assay between Apr 1, 2021-August 31, 2022 for TMB and MSI. We identified 65 patients who had neoplasms with documented TMB-High/MSI-High (n = 59) or TMB-High/MSI-Undetermined (n = 6) results as well as concurrent IHC results for MMR proteins [colorectal (n = 25), endometrial (n = 28), prostatic (n = 7), urothelial (n = 3), other (n = 5)]. The concordance between positive NGS TMB/MSI and MMR results was 98 %. Genetic/epigenetic alterations of MMR genes were documented in 78 % of the neoplasms. IHC studies for dMMR proteins revealed loss of MLH1/PMS2 (n = 33), MSH2/MSH6 (n = 14), MLH1/MSH2/PMS2 (n = 1), MLH1 (n = 1), MSH2 (n = 2), MSH6 (n = 6) and PMS2 (n = 6). All six prostatic neoplasms with dMMR had loss of MSH2/MSH6 (p < 0.0001). We conclude that neoplasms with positive results for TMB/MSI are highly concordant with positive dMMR results. Genetic/epigenetic alterations in the MMR genes are an underlying reason for most positive findings. The association of MSH2/MSH6 loss with prostatic neoplasms is of in-terest, but sample size is limited, and further studies are warranted to address this association.

Yang RK ，Alvarez H ，Lucas AS ，Roy-Chowdhuri S ，Rashid A ，Chen H ，Ballester LY ，Sweeney K ，Routbort MJ ，Patel KP ，Luthra R ，Medeiros LJ ，Toruner GA ... -  《Cancer Genetics》

Mitochondrial DNA copy number plays opposing roles in T-lymphocyte infiltration of colorectal cancer based on mismatch repair status: new directions for immunotherapy?

Chen M ，Liu H ，Liang W ，Huang P ，Ye F ，Cai Y ，Liang Z ，Xiong L ，Kang L ，Huang L ... -  《-》

Analysis of Concordance Between Next-Generation Sequencing Assessment of Microsatellite Instability and Immunohistochemistry-Mismatch Repair From Solid Tumors.

Ali-Fehmi R ，Krause HB ，Morris RT ，Wallbillich JJ ，Corey L ，Bandyopadhyay S ，Kheil M ，Elbashir L ，Zaiem F ，Quddus MR ，Abada E ，Herzog T ，Karnezis AN ，Antonarakis ES ，Kasi PM ，Wei S ，Swensen J ，Elliott A ，Xiu J ，Hechtman J ，Spetzler D ，Abraham J ，Radovich M ，Sledge G ，Oberley MJ ，Bryant D ... -  《JCO Precision Oncology》

Defining the optimum strategy for identifying adults and children with coeliac disease: systematic review and economic modelling.

Elwenspoek MM ，Thom H ，Sheppard AL ，Keeney E ，O'Donnell R ，Jackson J ，Roadevin C ，Dawson S ，Lane D ，Stubbs J ，Everitt H ，Watson JC ，Hay AD ，Gillett P ，Robins G ，Jones HE ，Mallett S ，Whiting PF ... -  《-》