Neurotrophic
tropomyosin receptor
kinase (NTRK) gene fusions are emerging tissue-agnostic drug targets in
malignancies including
colorectal carcinomas (
CRCs), but their detailed landscape in the context of various colorectal
carcinogenesis pathways remains to be investigated. In this study, pan-
tropomyosin receptor
kinase (TRK)
protein expression was assessed by immunohistochemistry (IHC) in retrospectively collected colorectal epithelial
tumor tissues, including 441
CRCs [133
microsatellite instability-high (MSI-high) and 308 microsatellite stable (MSS)] and 595 premalignant colorectal lesions (330 serrated lesions and 265 conventional
adenomas). TRK-positive cases were then subjected to next-generation sequencing and/or fluorescence in situ hybridization to confirm NTRK rearrangements. TRK IHC positivity was not observed in any of the MSS
CRCs, conventional
adenomas, traditional serrated
adenomas, or hyperplastic
polyps, whereas TRK positivity was observed in 11 of 58 (19%) MLH1-methylated MSI-high
CRCs, 4 of 23 (17%) sessile serrated lesions with dysplasia (SSLDs), and 5 of 132 (4%) sessile serrated lesions (SSLs). The 11 TRK-positive MSI-high
CRCs commonly harbored CpG island methylator phenotype-high (CIMP-high), MLH1 methylation, BRAF/KRAS wild-type, and NTRK1 or NTRK3 fusion (TPM3-NTRK1, TPR-NTRK1, LMNA-NTRK1, SFPQ-NTRK1, ETV6-NTRK3, or EML4-NTRK3). Both NTRK1 or NTRK3 rearrangement and BRAF/KRAS wild-type were detected in all nine TRK-positive SSL(D)s, seven of which demonstrated MSS and/or CIMP-low. TRK expression was selectively observed in distorted serrated crypts within SSLs and was occasionally localized at the base of serrated crypts. NTRK fusions were detected only in SSLs of patients aged ≥50 years, whereas BRAF mutation was found in younger age-onset SSLs. In conclusion, NTRK-rearranged
colorectal tumors develop exclusively through the serrated
neoplasia pathway and can be initiated from non-dysplastic SSLs without BRAF/KRAS mutations prior to full occurrence of MSI-high/CIMP-high. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.