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

Salins, Astrid Guyot d’Asnières de; Tachon, Gaëlle; Cohen, Romain; Karayan‐Tapon, Lucie; Junca, Audelaure; Frouin, Éric; Godet, Julie; Evrard, Camille; Randrian, Violaine; Duval, Alex; Svrcek, Magali; Lascols, Olivier; Vignot, Stéphane; Coulet, Florence; Thewis, André; Fléjou, Jean‐François; Cervera, Pascale; Tougeron, David

doi:10.1016/j.esmoop.2021.100120

Cited by 62 publications

(61 citation statements)

References 52 publications

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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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“…Discrepancies between MSI status and dMMR status exist even though both tests have high sensitivity and specificity. It is a rare phenomenon (1 to 2%), and most “false” discrepancies are due to common errors, for example poor quality of tissue sampling and/or poor quality of tissue fixation and staining [ 7 , 27 ]. Nevertheless, “true” discrepancies have been described when an inactive mutated MMR protein could remain expressed (missense mutation) but with a loss of function leading to a pMMR/MSI tumor [ 28 ].…”

Section: Consequences Of Mismatch Repair Deficiencymentioning

confidence: 99%

“…dMMR/MSI status dramatically increases tumor mutational burden [ 27 , 29 ]. In a study comparing the sequenced DNA of ten dMMR cancers with nine pMMR cancers (both colorectal and non-colorectal cancers), dMMR status resulted in a mean of 1782 somatic mutations per tumor as compared to 73 mutations per tumor in pMMR cancers [ 30 ].…”

Section: Consequences Of Mismatch Repair Deficiencymentioning

confidence: 99%

Microsatellite Instability in Colorectal Cancers: Carcinogenesis, Neo-Antigens, Immuno-Resistance and Emerging Therapies

Randrian

Evrard

Tougeron

2021

Cancers

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A defect in the DNA repair system through a deficient mismatch repair system (dMMR) leads to microsatellite instability (MSI). Microsatellites are located in both coding and non-coding sequences and dMMR/MSI tumors are associated with a high mutation burden. Some of these mutations occur in coding sequences and lead to the production of neo-antigens able to trigger an anti-tumoral immune response. This explains why non-metastatic MSI tumors are associated with high immune infiltrates and good prognosis. Metastatic MSI tumors result from tumor escape to the immune system and are associated with poor prognosis and chemoresistance. Consequently, immune checkpoint inhibitors (ICI) are highly effective and have recently been approved in dMMR/MSI metastatic colorectal cancers (mCRC). Nevertheless, some patients with dMMR/MSI mCRC have primary or secondary resistance to ICI. This review details carcinogenesis and the mechanisms through which MSI can activate the immune system. After which, we discuss mechanistic hypotheses in an attempt to explain primary and secondary resistances to ICI and emerging strategies being developed to overcome this phenomenon by targeting other immune checkpoints or through vaccination and modification of microbiota.

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“…Both methods could be used, but some studies have shown discordances between MMR protein IHC and MSI molecular testing, with rates ranging from 1% to 10% [ 22 , 23 , 24 ]. Expert centers usually perform both tests.…”

Section: Criteria To Identify and Diagnose Lynch Syndromementioning

confidence: 99%

Endoscopy to Diagnose and Prevent Digestive Cancers in Lynch Syndrome

Olivier

Randrian

Tougeron

et al. 2021

Cancers

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Lynch syndrome patients could benefit from various recommendations to prevent digestive cancers. In this review, we summarize the criteria to identify Lynch syndrome in patients with digestive cancers. We detail endoscopic screening procedures in patients with Lynch syndrome for gastric, small bowel, pancreatic, and colorectal cancers. We review the precise modalities of endoscopic follow-up, particularly the discrepancies that exist between the guidelines of the various scientific societies. We discuss the treatment of colorectal cancers in Lynch syndrome cases and patient adherence to endoscopic follow-up programs.

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

Cited by 62 publications

References 52 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

Microsatellite Instability in Colorectal Cancers: Carcinogenesis, Neo-Antigens, Immuno-Resistance and Emerging Therapies

Endoscopy to Diagnose and Prevent Digestive Cancers in Lynch Syndrome

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