NTRK oncogenic fusions are exclusively associated with the serrated neoplasia pathway in the colorectum and begin to occur in sessile serrated lesions

Abstract

Background: NTRK fusions are emerging tissue-agnostic drug targets in malignancies including colorectal cancers (CRCs), but their detailed landscape in the context of various colorectal carcinogenesis pathways remains to be investigated. Methods: Pan-TRK expression was assessed by immunohistochemistry in retrospectively collected colorectal epithelial tumor tissues, including 441 CRCs (133 microsatellite instability-high (MSI-high) and 308 microsatellite stable (MSS)) and 565 premalignant colorectal lesions (300 serrated lesions and 265 conventional adenomas). TRK-positive cases were subjected to next-generation sequencing and/or fluorescence in situ hybridization to confirm NTRK rearrangements. Results: TRK 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%) sporadic MSI-high CRCs, 4 of 23 (17%) sessile serrated lesions with dysplasia (SSLDs), and 5 of 132 (4%) SSLs. The 11 TRK-positive MSI-high CRCs commonly harbored CpG island methylator phenotype-high (CIMP-high), MLH1 methylation, KRAS/BRAF 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 KRAS/BRAF wild-type were detected in all nine TRK-positive SSL(D)s, seven of which demonstrated MSS and/or CIMP-low. TRK overexpression and early dysplastic changes are occasionally co-localized in the crypt base area of SSLs. Age-related occurrence patterns suggest that the progression interval from NTRK-rearranged SSLs to CRCs may be shorter than from BRAF-mutated SSLs to CRCs. Conclusion: NTRK-rearranged colorectal tumors develop exclusively through the serrated neoplasia pathway and can be initiated from non-dysplastic SSLs without KRAS/BRAF mutations prior to full occurrence of MSI-high/CIMP-high.

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

“…Additionally, several other NGS-based studies have suggested 2.6-7.3% occurrence of NTRK fusions in dMMR/MSI CRCs [15,16,18,20,21]. 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).…”

“…Westphalen et al found CRC to be the only cancer type in which NTRK fusions are associated with sporadic MSI [7]. Interestingly, Kim et al have recently described that NTRK fusions in CRC develop along the serrated pathway, in which sporadic dMLH1 is a major molecular event, and these fusions can already be present in premalignant sessile serrated lesions [19]. Additionally, several other NGS-based studies have suggested 2.6-7.3% occurrence of NTRK fusions in dMMR/MSI CRCs [15,16,18,20,21].…”

MiR-107 inhibits the malignant biological behavior of esophageal squamous cell carcinoma by targeting TPM3

“…On the other hand, some studies have revealed that miR-107 promotes cancer progression by inhibiting Phosphatase and Tensin Homolog Deleted on Chromosome Ten (PTEN) expression (40,41). As for TPM3, considerable research attention has been paid to the fact that TPM3 can participate in gene fusion and rearrangement, such as TPM3-NTRKs (10,11,42), TPM3-ROS1 (12,43), and so on. Although the proportion is not high, TPM3 rearrangement is often accompanied by special therapeutic effects (44,45).…”

“…The TPM3 protein can interact with actin, affecting muscle cell contraction and other cytoskeletal activity (8,9). Meanwhile, TPM3 gene-related rearrangement has been widely reported in malignant tumors and other diseases, such as colorectal cancer, thyroid cancer, and lung cancer (10)(11)(12). Some proteomics-based studies have found that TPM3 expression is abnormal in a variety of cancers and may influence tumor behaviors and therapeutic resistance (13)(14)(15).…”

And the story goes on: non-conventional dysplasia of the colorectum

“…As a matter of topical interest and therapeutic relevance, findings of a recent study by Kim et al [5] concluded that NTRK-rearranged colorectal carcinomas progress exclusively via the serrat-ed pathway of neoplasia, thus expanding the molecular landscape of serrated colorectal lesions. To the best of our knowledge, oncogenic gene fusions including NTRK fusions have yet to be studied in serrated lesions in IBD, and would indeed form an interesting research question.…”