1. 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
- Author
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Benoit Terris, Jean Roudié, Aude Aline-Fardin, Mélanie Cariou, Claire Bocciarelli, Laurent Doucet, Jean-Philippe Merlio, Laura Samaison, David Cappellen, Charline Caumont, Arnaud Uguen, and Pascale Marcorelles
- Subjects
Male ,0301 basic medicine ,Pathology ,Colorectal cancer ,Cost-Benefit Analysis ,DNA Mutational Analysis ,medicine.disease_cause ,0302 clinical medicine ,In Situ Hybridization, Fluorescence ,Aged, 80 and over ,Mutation ,Kinase ,Middle Aged ,Immunohistochemistry ,Molecular Diagnostic Techniques ,030220 oncology & carcinogenesis ,Female ,Microsatellite Instability ,France ,Gene Fusion ,Colorectal Neoplasms ,MutL Protein Homolog 1 ,Proto-Oncogene Proteins B-raf ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,In situ hybridization ,Adenocarcinoma ,Biology ,Real-Time Polymerase Chain Reaction ,MLH1 ,Pathology and Forensic Medicine ,03 medical and health sciences ,Predictive Value of Tests ,Biomarkers, Tumor ,medicine ,ROS1 ,Humans ,False Positive Reactions ,Genetic Predisposition to Disease ,neoplasms ,Aged ,Automation, Laboratory ,Sequence Analysis, RNA ,Reproducibility of Results ,Microsatellite instability ,medicine.disease ,digestive system diseases ,Genes, ras ,030104 developmental biology ,Feasibility Studies - Abstract
Summary Targetable kinase fusions are extremely rare ( We searched for NTRK1, NTRK2, NTRK3, ALK, ROS1, BRAF, RET, and NRG1 kinase fusions in CRCs using methods easy-to-implement in pathology laboratories: immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), and fully automated real-time PCR targeted analyses. RNA-sequencing analyses were used for confirmation. Among 84 selected MLH1 deficient (IHC) CRCs cases, MLH1loss MSI-High wild-type CRCs consisted first in 19 cases after Idylla™ analyses and finally in 18 cases (21%) after RNA-sequencing (detection of one additional KRASG12D mutation). FISH (and when relevant, IHC) analyses concluded in 5 NTRK1, 3 NTRK3, 1 ALK, 2 BRAF, and 2 RET FISH positive tumors. ALK and NTRK1 rearranged tumors were IHC positive, but pan-TRK IHC was negative in the 3 NTRK3 FISH positive tumors. RNA-sequencing analyses confirmed 12 of 13 fusions with only one false positive RET FISH result. Finally, 12/18 (67%) of MLH1loss MSI-High wild-type CRCs contained targetable kinase fusions. Our study demonstrates the feasibility, but also the cost-effectiveness, of a multistep but rapid diagnostic strategy based on nonsequencing methods to identify rare and targetable kinase fusions in patients with advanced CRCs, as well as the high prevalence of these kinase fusions in MLH1loss MSI-High wild-type CRCs. Nevertheless, confirmatory RNA-sequencing analyses are necessary in case of low FISH positive nuclei percentage to rule out FISH false-positive results.
- Published
- 2021
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