MSI-High RAS-BRAF wild-type colorectal adenocarcinomas with MLH1 loss have a high frequency of targetable oncogenic gene fusions whose diagnoses are feasible using methods easy-to-implement in pathology laboratories

Bocciarelli, Claire; Caumont, Charline; Samaison, Laura; Cariou, Mélanie; Aline-Fardin, Aude; Doucet, Laurent; Roudié, Jean; Terris, Benoı̂t; Merlio, Jean-Philippe; Marcorelles, Pascale; Cappellen, David; Uguen, Arnaud

doi:10.1016/j.humpath.2021.05.006

Cited by 19 publications

(18 citation statements)

References 27 publications

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“…In the dMLH1/BRAFV600Ewt subgroup, frequency of NTRK fusions has been reported to be 5-28% [4,16,17] and in the subgroup of dMLH1/MLH1ph 14-19% [18,19], which are in line with our frequencies of 11% (7/62) and 16% (7/43), respectively. Yet other studies have reported NTRK fusions to occur in dMLH1/BRAFV600Ewt/MLH1ph/RASwt subgroup of CRC with as high frequency as 17-44% [15][16][17][18]22] being comparable to our prevalence of 23.3% (7/30).…”

Section: Discussionsupporting

confidence: 90%

“…Thus, our NTRK fusion frequency of 0.34% (7/2079) is at the higher end. NTRK1 fusions with TPM3, LMNA and TPR partners have been shown to be the most common ones in CRC [6,7] and PLEKHA6::NTRK1 fusions have also previously been described in this disease [17,18]. Of these, we found NTRK1 to partner with TPM3, LMNA and PLEKHA6.…”

Section: Discussionsupporting

confidence: 62%

“…Furthermore, our study shows that specificity and sensitivity of pan-TRK IHC are optimal in CRC samples. Although specificity of this method varies between different tumour Original magnification 400 × types, it has previously been reported to be 100% for pan-TRK in CRC [4,13,17,24]. Pan-TRK IHC positive CRCs are characterised by cytoplasmic staining with additional positivity in other subcellular compartments in a fusion partner-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

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Gene fusions and oncogenic mutations in MLH1 deficient and BRAFV600E wild-type colorectal cancers

et al. 2022

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Gene fusions can act as oncogenic drivers and offer targets for cancer therapy. Since fusions are rare in colorectal cancer (CRC), their universal screening seems impractical. Our aim was to investigate gene fusions in 62 CRC cases with deficient MLH1 (dMLH1) and BRAFV600E wild-type (wt) status from a consecutive real-life series of 2079 CRCs. First, gene fusions were analysed using a novel FusionPlex Lung v2 RNA–based next-generation sequencing (NGS) panel, and these results were compared to a novel Idylla GeneFusion assay and pan-TRK immunohistochemistry (IHC). NGS detected seven (7/62, 11%) NTRK1 fusions (TPM3::NTRK1, PLEKHA6::NTRK1 and LMNA::NTRK1, each in two cases, and IRF2BP2::NTRK1 in one case). In addition, two ALK, four RET and seven BRAF fusions were identified. Idylla detected seven NTRK1 expression imbalances, in line with the NGS results (overall agreement 100%). Furthermore, Idylla detected the two NGS–identified ALK rearrangements as one specific ALK fusion and one ALK expression imbalance, whilst only two of the four RET fusions were discovered. However, Idylla detected several expression imbalances of ALK (n = 7) and RET (n = 1) that were found to be fusion negative with the NGS. Pan-TRK IHC showed clearly detectable, fusion partner-dependent staining patterns in the seven NTRK1 fusion cases. Overall agreement for pan-TRK antibody clone EPR17341 was 98% and for A7H6R 100% when compared to the NGS. Of the 62 CRCs, 43 were MLH1 promoter hypermethylated (MLH1ph) and 39 were RASwt. All fusion cases were both MLH1ph and RASwt. Our results show that kinase fusions (20/30, 67%) and most importantly targetable NTRK1 fusions (7/30, 23%) are frequent in CRCs with dMLH1/BRAFV600Ewt/MLH1ph/RASwt. NGS was the most comprehensive method in finding the fusions, of which a subset can be screened by Idylla or IHC, provided that the result is confirmed by NGS.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

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Gene fusions and oncogenic mutations in MLH1 deficient and BRAFV600E wild-type colorectal cancers

et al. 2022

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“…The cases included in this study were selected among patients with non‐CRC tumors requiring dMMR testing initially analyzed in Ouest Pathology laboratory. As performed in previous publications of our group, the same formalin‐fixed paraffin‐embedded tumor samples had been previously used for successive IHC (MLH1, MSH2, MSH6, and PMS2) and molecular analyses including external testing in a molecular pathology platform (using fragment‐length polymorphism analysis of five microsatellites: BAT26, BAT25, NR21, NR22 , and NR24 ) and before the complementary in‐house Idylla MSI test performed in the present work 10,19,23 . The clinical evolution of the patients and their genetics background in terms of potential Lynch syndromes were not taken into account in this work dedicated to the comparison of diagnostic methods.…”

Section: Methodsmentioning

confidence: 99%

“…Several studies have reported about the performances of the Idylla MSI test (Biocartis) that allows fully‐automated and rapid (2.5 h) MSI testing and is usable even in pathology laboratories with no expertise in molecular pathology. These studies have particularly reported on the good performances of this test in CRC samples (about 98% sensitivity and 99% specificity about 2000 CRC samples tested in the literature) 9–13,15–20,22,23 . Series of non‐CRC tumors (about 1000 cases including several different organs and tumor types, as endometrial, urothelial, gastric, but also fewer duodenal–pancreatic, ovarian, prostatic, small‐intestine carcinomas, or cutaneous adnexal tumors) have also reported good performances of this Idylla MSI test with nervertheless inferior sensitivity in comparison with CRC (about 92% sensitivity and 99% specificity in non‐CRC tumors) 6–9,11,12,14,15,18,21,23,24 .…”

Section: Introductionmentioning

confidence: 93%

Idylla MSI test combined with immunohistochemistry is a valuable and cost effective strategy to search for microsatellite instable tumors of noncolorectal origin

Samaison

Uguen

2022

Pathology International

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Recent diagnostic and therapeutic progresses have increased the need of searching for microsatellite instability (MSI) in cancer samples beyond colorectal cancer (CRC) ones. The availability of the fully‐automated Idylla MSI test (Biocartis), implementable easily in pathology laboratories, offers the opportunity to reconsider MSI diagnostic strategies towards rapid and in‐house diagnosis. In this study, we evaluate the performances and cost‐effectiveness of an in‐house Idylla MSI testing in comparison with an externalized testing of about 54 non‐CRC tumor samples. The Idylla MSI test concluded in valid analyses in 53/54 (98.1%) tumor samples with MSI statuses concordant with external molecular and immunohistochemical testing in 50/53 (94.3%) samples. Wrong Idylla MSI test results were obtained in 3/53 (5.7%) samples. Manual checking of microsatellite analyses results and confrontation between the results of Idylla and immunohistochemical analyses have permitted detection and correction of the discrepancies. The implementation of an in‐house Idylla MSI testing for non‐CRC tumors, necessarily combined with immunohistochemistry searching for MSI tumors, appeared not only valuable in terms of performances, but also in terms of cost‐effectiveness without increasing the analyses‐related costs but decreasing dramatically their turnaround times to one single working day.

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Diagnostic mutationnel rapide Idylla™ : applications théranostiques actuelles et futures

Bourhis¹,

Remoué²,

Samaison³

et al. 2022

Annales de Pathologie

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MSI-High RAS-BRAF wild-type colorectal adenocarcinomas with MLH1 loss have a high frequency of targetable oncogenic gene fusions whose diagnoses are feasible using methods easy-to-implement in pathology laboratories

Cited by 19 publications

References 27 publications

Gene fusions and oncogenic mutations in MLH1 deficient and BRAFV600E wild-type colorectal cancers

Gene fusions and oncogenic mutations in MLH1 deficient and BRAFV600E wild-type colorectal cancers

Idylla MSI test combined with immunohistochemistry is a valuable and cost effective strategy to search for microsatellite instable tumors of noncolorectal origin

Diagnostic mutationnel rapide Idylla™ : applications théranostiques actuelles et futures

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