Oncotarget

Clinical Research Papers:

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

Do Youn Park, Chan Choi, Eunji Shin, Jae Hyuk Lee, Chae Hwa Kwon, Hong-Jae Jo, Hyeong-Rok Kim, Hyun Sung Kim, Nahmgun Oh, Ji Shin Lee, Ok Ku Park, Eok Park, Jonghoon Park, Jong-Yeon Shin, Jong-Il Kim, Jeong-Sun Seo, Hee Dong Park and Joonghoon Park _

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Oncotarget. 2016; 7:8399-8412. https://doi.org/10.18632/oncotarget.6724

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Abstract

Do Youn Park1,*, Chan Choi3,*, Eunji Shin8, Jae Hyuk Lee3, Chae Hwa Kwon1, Hong-Jae Jo2, Hyeong-Rok Kim4, Hyun Sung Kim2, Nahmgun Oh2, Ji Shin Lee3, Ok Ku Park8, Eok Park8, Jonghoon Park8, Jong-Yeon Shin5, Jong-Il Kim5,6, Jeong-Sun Seo5,6,7, Hee Dong Park8 and Joonghoon Park8

1 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

2 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

3 Department of Pathology, Chonnam National University Hwasun Hospital, Hwasun-gun, Jeollanam-do, Republic of Korea

4 Department of Surgery, Chonnam National University Hwasun Hospital, Hwasun-gun, Jeollanam-do, Republic of Korea

5 Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul, Republic of Korea

6 Department of Biochemical and Molecular Biology, Seoul National University College of Medicine, Seoul, Republic of Korea

7 Macrogen Inc., Seoul, Republic of Korea

8 LG Life Sciences Ltd., R&D Park, Daejeon, Republic of Korea

* These authors have contributed equally to this work

Correspondence to:

Joonghoon Park, email:

Keywords: NTRK1 fusion, Korean colon cancer, RNA-seq, predictive biomarker, targeted therapy

Received: September 11, 2015 Accepted: December 07, 2015 Published: December 22, 2015

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.


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