title: NTRK1 fusions for the therapeutic intervention of Korean patients with colon cancer.
abstract: 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.
authors.affiliation: Department of Pathology, Pusan National University Hospital and Pusan National University School of Medicine, and BioMedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea.
authors.forename: Do Youn
authors.initials: DY
authors.lastname: Park
authors.affiliation: Department of Pathology, Chonnam National University Hwasun Hospital, Hwasun-gun, Jeollanam-do, Republic of Korea.
authors.forename: Chan
authors.initials: C
authors.lastname: Choi
authors.affiliation: LG Life Sciences Ltd., R&D Park, Daejeon, Republic of Korea.
authors.forename: Eunji
authors.initials: E
authors.lastname: Shin
authors.affiliation: Department of Pathology, Chonnam National University Hwasun Hospital, Hwasun-gun, Jeollanam-do, Republic of Korea.
authors.forename: Jae Hyuk
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Pathology, Pusan National University Hospital and Pusan National University School of Medicine, and BioMedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea.
authors.forename: Chae Hwa
authors.initials: CH
authors.lastname: Kwon
authors.affiliation: Department of Surgery, Pusan National University Hospital and Pusan National University School of Medicine, and BioMedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea.
authors.forename: Hong-Jae
authors.initials: HJ
authors.lastname: Jo
authors.affiliation: Department of Surgery, Chonnam National University Hwasun Hospital, Hwasun-gun, Jeollanam-do, Republic of Korea.
authors.forename: Hyeong-Rok
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Department of Surgery, Pusan National University Hospital and Pusan National University School of Medicine, and BioMedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea.
authors.forename: Hyun Sung
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Surgery, Pusan National University Hospital and Pusan National University School of Medicine, and BioMedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea.
authors.forename: Nahmgun
authors.initials: N
authors.lastname: Oh
authors.affiliation: Department of Pathology, Chonnam National University Hwasun Hospital, Hwasun-gun, Jeollanam-do, Republic of Korea.
authors.forename: Ji Shin
authors.initials: JS
authors.lastname: Lee
authors.affiliation: LG Life Sciences Ltd., R&D Park, Daejeon, Republic of Korea.
authors.forename: Ok Ku
authors.initials: OK
authors.lastname: Park
authors.affiliation: LG Life Sciences Ltd., R&D Park, Daejeon, Republic of Korea.
authors.forename: Eok
authors.initials: E
authors.lastname: Park
authors.affiliation: LG Life Sciences Ltd., R&D Park, Daejeon, Republic of Korea.
authors.forename: Jonghoon
authors.initials: J
authors.lastname: Park
authors.affiliation: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul, Republic of Korea.
authors.forename: Jong-Yeon
authors.initials: JY
authors.lastname: Shin
authors.affiliation: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul, Republic of Korea.|Department of Biochemical and Molecular Biology, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jong-Il
authors.initials: JI
authors.lastname: Kim
authors.affiliation: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul, Republic of Korea.|Department of Biochemical and Molecular Biology, Seoul National University College of Medicine, Seoul, Republic of Korea.|Macrogen Inc., Seoul, Republic of Korea.
authors.forename: Jeong-Sun
authors.initials: JS
authors.lastname: Seo
authors.affiliation: LG Life Sciences Ltd., R&D Park, Daejeon, Republic of Korea.
authors.forename: Hee Dong
authors.initials: HD
authors.lastname: Park
authors.affiliation: LG Life Sciences Ltd., R&D Park, Daejeon, Republic of Korea.
authors.forename: Joonghoon
authors.initials: J
authors.lastname: Park
mesh_terms: D000368:Aged; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D063646:Carcinogenesis; D016022:Case-Control Studies; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D000077547:Crizotinib; D005260:Female; D005500:Follow-Up Studies; D005663:Furans; D050939:Gene Fusion; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009367:Neoplasm Staging; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020917:Receptor, trkA / Q000235:genetics* / Q000378:metabolism*; D056910:Republic of Korea; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014335:Tropomyosin / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D002227:Carbazoles; D005663:Furans; C494847:LMNA protein, human; D034904:Lamin Type A; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D012333:RNA, Messenger; C498783:TPM3 protein, human; D014335:Tropomyosin; D000077547:Crizotinib; C119379:lestaurtinib; D020917:Receptor, trkA
keywords: Korean colon cancer; NTRK1 fusion; RNA-seq; predictive biomarker; targeted therapy