Receptor tyrosine kinase fusions act as a significant alternative driver of the serrated pathway in colorectal cancer development

Abstract

Serrated polyps are a clinically and molecularly heterogeneous group of lesions that can contribute to the development of colorectal cancers (CRCs). However, the molecular mechanism underlying the development of serrated lesions is still not well understood. Here, we combined multiple approaches to analyze the genetic alterations in 86 colorectal adenomas (including 35 sessile serrated lesions, 15 traditional adenomas, and 36 conventional adenomatous polyps). We also investigated the in vitro and in vivo oncogenic properties of a novel variant of the NCOA4-RET fusion gene. Molecular profiling revealed that sessile serrated lesions and traditional serrated adenomas have distinct clinicopathological and molecular features. Moreover, we identified receptor tyrosine kinase translocations exclusively in sessile serrated lesions (17%), and the observation was validated in a separate cohort of 34 sessile serrated lesions (15%). The kinase fusions as well as the BRAF and KRAS mutations were mutually exclusive to each other. Ectopic expression of a novel variant of the NCOA4-RET fusion gene promoted cell proliferation in vitro and in vivo, and the proliferation was significantly suppressed by RET kinase inhibitors. All of these underscored the importance of mitogen-activated protein kinase (MAPK) pathway activation in the serrated pathway of colorectal tumorigenesis. In addition, we demonstrated that the kinase fusion may occur early in the precursor lesion and subsequent loss of TP53 may drives the transformation to carcinoma during serrated tumorigenesis. In conclusion, we identified kinase fusions as a significant alternative driver of the serrated pathway in colorectal cancer development, and detecting their presence may serve as a biomarker for the diagnosis of sessile serrated lesions.

ERBB2 Mutations as Potential Predictors for Recurrence in Colorectal Serrated Polyps by Targeted Next-Generation Sequencing

“…In line with previous studies, our findings recognized BRAF V600E or KRAS mutations as the triggering event of the serrated pathway ( 27 ). The overall rate of BRAF V600E (53/90, 59%) was within the range reported in the existing literatures from 50% to 83% ( 28 , 29 ). The high level of mutant BRAF in SPs is becoming growingly relevant as a poor prognostic factor ( 30 ).…”

NTRK fusion‐positive colorectal cancer in Japanese population

“…15,17,18 Interestingly, a recent study showed that a subset of sessile serrated lesions harbor RTK fusions. 19 Although no NTRK fusions were identified in this study, the high frequency of MMR deficiency in RTK fusionpositive colorectal cancers might imply their relationship to the serrated pathway of tumorigenesis.…”

Evolving pathologic concepts of serrated lesions of the colorectum

“…According to data from Western countries including the United States, Canada, Australia, Germany, Austria, and Switzerland, frequencies of BRAF V600E mutations in SSLs range from 63% to 100% ( Supplementary Table S1) [22,24,[33][34][35][36][37][38][39][40][41]. However, in East Asian countries, including South Korea, Japan, and China, BRAF mutation frequencies in SSLs have been reported to be relatively lower, ranging from 14% to 86% (Supplementary Table S1) [42][43][44][45][46][47][48][49][50][51][52][53][54][55]. Using these data, we conducted a pooled analysis to directly compare the frequencies of BRAF mutations in SSLs between Western and Eastern countries (Table 2).…”