NTRK gene rearrangements are highly enriched in MLH1/PMS2 deficient, BRAF wild-type colorectal carcinomas-a study of 4569 cases.
Adult
Aged
Biomarkers, Tumor
/ genetics
Colorectal Neoplasms
/ genetics
Female
Gene Rearrangement
Humans
Male
Middle Aged
Mismatch Repair Endonuclease PMS2
/ genetics
MutL Protein Homolog 1
/ genetics
Oncogene Proteins, Fusion
/ genetics
Proto-Oncogene Proteins B-raf
/ genetics
Receptor, trkA
/ genetics
Journal
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
ISSN: 1530-0285
Titre abrégé: Mod Pathol
Pays: United States
ID NLM: 8806605
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
25
09
2019
accepted:
21
10
2019
revised:
19
10
2019
pubmed:
4
12
2019
medline:
7
4
2021
entrez:
4
12
2019
Statut:
ppublish
Résumé
NTRK gene rearrangements are important to identify as predictors of response to targeted therapy in many malignancies. Only 0.16-0.3% of colorectal carcinomas (CRCs) harbor these fusions making universal screening difficult. We therefore investigated whether pan-Trk immunohistochemistry (IHC), mismatch repair deficiency (MMRd), and BRAFV600E mutation status could be used to triage molecular testing for NTRK gene rearrangements in CRC. CRCs from 4569 unselected patients underwent IHC in TMA format with two different anti-pan-Trk rabbit monoclonal antibodies. All positive cases were confirmed on whole sections and underwent RNA-sequencing. Pan-Trk IHC was positive in 0.2% of CRCs (9/4569). Both antibodies demonstrated similar staining characteristics with diffuse positive staining in all neoplastic cells. Of note 8/9 (89%) IHC positive cases were both MMRd (all showing MLH1/PMS2 loss) and lacked BRAFV600E mutation. That is, IHC was positive in 5.3% (8/152) MLH1/PMS2/BRAFV600E triple negative CRCs, but only 0.02% (1/4417) not showing this phenotype. All nine IHC positive CRCs demonstrated gene rearrangements (LMNA-NTRK1 in 5 CRCs, TPR-NTRK1, STRM-NTRK1, MUC2-NTRK2, and NTRK1 with an unknown partner in one each), suggesting close to 100% specificity for IHC in this sub-population. NTRK fusions were associated with right sided (p = 0.02), larger tumors (p = 0.029) with infiltrative growth (p = 0.021). As a part of universal Lynch syndrome screening many institutions routinely test all CRCs for MMRd, and then proceed to reflex BRAFV600E mutation testing in MLH1/PMS2 negative CRCs. We conclude that performing pan-Trk IHC on this preselected subgroup of MLH1/PMS2/BRAFV600E triple negative CRCs (only 3.3% of all CRC patients) is a resource effective approach to identify the overwhelming majority of CRC patients with NTRK gene fusions.
Identifiants
pubmed: 31792356
doi: 10.1038/s41379-019-0417-3
pii: S0893-3952(22)00870-5
doi:
Substances chimiques
Biomarkers, Tumor
0
MLH1 protein, human
0
Oncogene Proteins, Fusion
0
Receptor, trkA
EC 2.7.10.1
BRAF protein, human
EC 2.7.11.1
Proto-Oncogene Proteins B-raf
EC 2.7.11.1
PMS2 protein, human
EC 3.6.1.-
Mismatch Repair Endonuclease PMS2
EC 3.6.1.3
MutL Protein Homolog 1
EC 3.6.1.3
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
924-932Références
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