Characterization of atypical dMMR (deficient MisMatch Repair) tumors: A study from a large cohort of 4948 cases

Jaffrelot, Marion; Sèlves, Janick; Farés, Nadim; Staub, Anne; Laurenty, A.P.; Danjoux, Marie; Meilleroux, Julie; Chipoulet, Edith; Toulas, Christine; Guimbaud, Rosine

doi:10.1093/annonc/mdz269.033

Cited by 6 publications

(7 citation statements)

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“…Most tumors had MMR IHC tests (98.2%) and only 9 MSI/pMMR cases were identified (2.4%). These results were concordant with recent series ( Lindor et al, 2002 ; Watson et al, 2007 ; Fazzalari, 2017 ; Cohen et al, 2018 ; Jaffrelot et al, 2019 ; De Salins et al, 2021 ). A recent work showed that ∼6% of MSI cases retained mismatch repair protein expression and would consequently be missed by IHC testing alone, thereby hindering patient access to immunotherapy ( Hechtman et al, 2020 ).…”

Section: Discussionsupporting

confidence: 93%

“…Sensitivity and specificity of the Pentaplex panel range between 90 and 100% ( Xicola et al, 2007 ; Goel et al, 2010 ). Moreover, some studies have shown discordance between MMR IHC and MSI molecular testing, ranging from 1 to 10% ( Lindor et al, 2002 ; Watson et al, 2007 ; Jaffrelot et al, 2019 ; Guyot; De Salins et al, 2021 ). In our cohort, all tumors were initially determined as MSI using a robust test (Pentaplex panel) ( Suraweera et al, 2002 ; Wong et al, 2006 ).…”

Section: Discussionmentioning

confidence: 99%

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HSP110 as a Diagnostic but Not a Prognostic Biomarker in Colorectal Cancer With Microsatellite Instability

et al. 2022

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Determination of microsatellite instability (MSI) using molecular test and deficient mismatch repair (dMMR) using immunohistochemistry (IHC) has major implications on colorectal cancer (CRC) management. The HSP110 T17 microsatellite has been reported to be more monomorphic than the common markers used for MSI determination. Large deletion of HSP110 T17 has been associated with efficacy of adjuvant chemotherapy in dMMR/MSI CRCs. The aim of this study was to evaluate the interest of HSP110 deletion/expression as a diagnostic tool of dMMR/MSI CRCs and a predictive tool of adjuvant chemotherapy efficacy. All patients with MSI CRC classified by molecular testing were included in this multicenter prospective cohort (n = 381). IHC of the 4 MMR proteins was carried out. HSP110 expression was carried out by IHC (n = 343), and the size of HSP110 T17 deletion was determined by PCR (n = 327). In the 293 MSI CRCs with both tests, a strong correlation was found between the expression of HSP110 protein and the size of HSP110 T17 deletion. Only 5.8% of MSI CRCs had no HSP110 T17 deletion (n = 19/327). HSP110 T17 deletion helped to re-classify 4 of the 9 pMMR/MSI discordance cases as pMMR/MSS cases. We did not observe any correlation between HSP110 expression or HSP110 T17 deletion size with time to recurrence in patients with stage II and III CRC, treated with or without adjuvant chemotherapy. HSP110 is neither a robust prognosis marker nor a predictor tool of adjuvant chemotherapy efficacy in dMMR/MSI CRC. However, HSP110 T17 is an interesting marker, which may be combined with the other pentaplex markers to identify discordant cases between MMR IHC and MSI.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

HSP110 as a Diagnostic but Not a Prognostic Biomarker in Colorectal Cancer With Microsatellite Instability

et al. 2022

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“…They found a higher rate of discrepancy (9.8%) but did not provide any explanations, other than that the tests were re-done in a more experienced reference center. Finally, Jaffrelot et al 24 reported a 1.1% discordance rate in a large cohort of 2528 different cancers, using IHC of the four MMR proteins and Pentaplex tests. The rate of discordance was equivalent to our study even though molecular MSI testing is known to have lower performances in malignancies other than CRC.…”

Section: Discussionmentioning

confidence: 99%

“…48 As in our study, rare MSI cases with the presence of all four proteins in IHC have been described in the literature. 20,21,24 A recent work showed that~6% of MSI cases retained mismatch repair protein expression and that these would be missed by IHCbased testing, thereby hindering patient access to immunotherapy. 49 The majority of these cases harbor germline or somatic mismatch repair gene missense mutations; consequently inactive mutant proteins remain detected by IHC.…”

Section: Discussionmentioning

confidence: 99%

“…17,18 Some studies have shown discordance between MMR IHC and MSI molecular testing, ranging from 1% to 10%. [19][20][21][22][23][24] All of these studies used relatively old techniques for MMR/MSI determination (fewer than five microsatellite markers) and/ or were conducted with a low number of patients (<1000 with CRCs). Failure in determining the MMR/MSI status has a major impact on therapeutic strategy, especially on eligibility for ICI treatment.…”

Section: Introductionmentioning

confidence: 99%

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Discordance between immunochemistry of mismatch repair proteins and molecular testing of microsatellite instability in colorectal cancer

et al. 2021

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Background: DNA mismatch repair system deficiency (dMMR) is found in 15% of colorectal cancers (CRCs). Two methods are used to determine dMMR, immunohistochemistry (IHC) of MMR proteins and molecular testing of microsatellite instability (MSI). Only studies with a low number of patients have reported rates of discordance between these two methods, ranging from 1% to 10%. Materials and methods: Overall, 3228 consecutive patients with CRCs from two centers were included. Molecular testing was carried out using the Pentaplex panel and IHC evaluated four (MLH1, MSH2, MSH6, and PMS2; cohort 1; n ¼ 1085) or two MMR proteins (MLH1 and MSH2; cohort 2; n ¼ 2143). The primary endpoint was the rate of discordance between MSI and MMR IHC tests.Results: Fifty-one discordant cases (1.6%) were initially observed. Twenty-nine out of 51 discordant cases were related to IHC misclassifications. In cohort 1, after re-reading IHC and/or carrying out new IHC, 16 discordant cases were reclassified as nondiscordant. In cohort 2, after the addition of MSH6/PMS2 IHC and re-examination, 13 were reclassified as nondiscordant. In addition, 10 misclassifications of molecular tests were identified. Finally, only 12 discordant cases (0.4%) remained: 5 were proficient MMR/MSI and 7 were dMMR/microsatellite stable. Conclusions: Our study confirmed the high degree of concordance between MSI and MMR IHC tests. Discordant cases must be reviewed, and if needed, tests must be repeated and analyzed by an expert team.

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Immune Checkpoint Inhibitors in Luminal Gastrointestinal Malignancies: Going Beyond MSI-H/dMMR, TMB and PD-L1

2022

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In luminal gastrointestinal tumors, immune checkpoint inhibitors (ICIs) targeting PD-1, PD-L1 and CTLA-4 have been investigated in multiple settings. The indications for these drugs are primarily dependent on specific biomarkers that imply immunogenicity: overexpression of PD-L1, tumor mutational burden, loss of mismatch repair proteins (dMMR) and/or high microsatellite instability status. Although these markers can be both predictive and prognostic, there is variability in how they are measured and used to guide therapies. Moreover, the use of ICIs can be further refined with a better understanding of the tumor microenvironment and interactions with other available therapies. The purpose of this review is to characterize luminal gastrointestinal tumors’ responses to ICIs considering known predictive biomarkers and discuss emerging therapeutic approaches using ICIs.

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Characterization of atypical dMMR (deficient MisMatch Repair) tumors: A study from a large cohort of 4948 cases

Cited by 6 publications

References 0 publications

HSP110 as a Diagnostic but Not a Prognostic Biomarker in Colorectal Cancer With Microsatellite Instability

HSP110 as a Diagnostic but Not a Prognostic Biomarker in Colorectal Cancer With Microsatellite Instability

Discordance between immunochemistry of mismatch repair proteins and molecular testing of microsatellite instability in colorectal cancer

Immune Checkpoint Inhibitors in Luminal Gastrointestinal Malignancies: Going Beyond MSI-H/dMMR, TMB and PD-L1

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