NTRK1 fusions for the therapeutic intervention of Korean patients with colon cancer

The identification and clinical validation of cancer driver genes are essential to accelerate the translational transition of cancer genomics, as well as to find clinically confident targets for the therapeutic intervention of cancers. Here we identified recurrent LMNA-NTRK1 and TPM3-NTRK1 fusions in Korean patients with colon cancer (3 out of 147, 2%) through next-generation RNA sequencing (RNA-seq). NTRK1 fusions were mutually exclusive oncogenic drivers of colon cancer that were accompanied with in vitro potential of colony formation and in vivo tumorigenicity comparable to KM12, a human colon cancer cell line harboring TPM3-NTRK1 fusion. NTRK1-encoded TrkA protein was prevalent in 11 out of 216 Korean (5.1%) and 28 out of 472 Chinese patients (5.9%) from independent cohorts, respectively. The expression level of TrkA was significantly correlated with NTRK1 fusion (p = 0.0192), which was verified by a fluorescence in situ hybridization (FISH). Korean patients with TrkA-positive colon cancer had a marginal but significant shorter overall survival time than TrkA-negative colon cancer [hazard ratio (HR) = 0.5346, 95% confidential interval (CI) = 0.2548-0.9722, p = 0.0411]. In addition, KM12 cell line was sensitive to selective TrkA inhibitors. These results demonstrate that NTRK1 fusion is granted as a clinically relevant target for therapeutic intervention of colon cancer. Fresh frozen tissues resected between 2008 and 2012 from patients with primary colon cancer and matched normal controls were used in this study. Informed consent was obtained from all patients. Tumor tissues were selected according to the tumor sample inclusion criteria of the International Cancer Genome Consortium (ICGC). Briefly, tumor tissues composed of more than 60% of tumor cells and less than 20% of necrotic cells or normal cells on histological assessment were included. Tumor tissues from patients who had a family history of colon cancer were excluded. In total, 150 tumor and 50 matched normal tissues were analyzed.