Oncotarget

Research Papers:

Identification of a novel partner gene, KIAA1217, fused to RET: Functional characterization and inhibitor sensitivity of two isoforms in lung adenocarcinoma

Mi-Sook Lee, Ryong Nam Kim, Hoseok I, Doo-Yi Oh, Ji-Young Song, Ka-Won Noh, Yu-Jin Kim, Jung Wook Yang, Maruja E. Lira, Chang Hun Lee, Min Ki Lee, Yeoung Dae Kim, Mao Mao, Joungho Han, Jhingook Kim and Yoon-La Choi _

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Oncotarget. 2016; 7:36101-36114. https://doi.org/10.18632/oncotarget.9137

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Abstract

Mi-Sook Lee1,2,*, Ryong Nam Kim3,4,*, Hoseok I5,6, Doo-Yi Oh1,2, Ji-Young Song2, Ka-Won Noh1,2, Yu-Jin Kim1,2, Jung Wook Yang11, Maruja E. Lira7, Chang Hun Lee8, Min Ki Lee9, Yeoung Dae Kim5, Mao Mao7,13, Joungho Han10, Jhingook Kim12, Yoon-La Choi1,2,10

1Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, Seoul, Korea

2Laboratory of Cancer Genomics and Molecular Pathology, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea

3Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Korea

4Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, Korea

5Department of Thoracic and Cardiovascular Surgery, Pusan National University School of Medicine, Busan, Korea

6Pusan National University Hospital Biomedical Research Institute, Busan, Korea

7Pfizer Oncology, San Diego, California, USA

8Department of Pathology, Pusan National University School of Medicine, Busan, Korea

9Department of Pulmonology Allergy and Critical Care Medicine, Pusan National University School of Medicine, Busan, Korea

10Departments of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University College of Medicine, Seoul, Korea

11Department of Pathology, Gyeongsang National University School of Medicine, Jinju, Korea

12Department of Thoracic Surgery, Samsung Medical Center, Sungkyunkwan University College of Medicine, Seoul, Korea

13Present address: BGI Genomics, Shenzhen, China

*These authors contributed equally to this work

Correspondence to:

Yoon-La Choi, email: [email protected]

Jhingook Kim, email: [email protected]

Keywords: lung cancer, RET, KIAA1217, KIAA1217-RET fusion, oncogenic driver

Received: November 16, 2015     Accepted: April 16, 2016     Published: May 02, 2016

ABSTRACT

REarranged during Transfection (RET) fusion genes are detected in approximately 1% of lung adenocarcinomas and known primarily as oncogenic driver factors. Here, we found a novel RET fusion gene, KIAA1217-RET, and examined the functional differences of RET51 and RET9 protein, fused with KIAA1217 in cancer progression and drug response. KIAA1217-RET, resulting from the rearrangement of chromosome 10, was generated by the fusion of KIAA1217 exon 11 and RET exon 11 from a non-small cell lung cancer patient. Expression of this gene led to increased cell growth and invasive properties through activations of the PI3K/AKT and ERK signaling pathways and subsequently enabled oncogenic transformation of lung cells. We observed that cells expressing KIAA1217-RET9 fusion protein were more sensitive to vandetanib than those expressing KIAA1217-RET51 and both isoforms attenuated cellular growth via cell cycle arrest. These results demonstrated that KIAA1217-RET fusion represents a novel oncogenic driver gene, the products of which are sensitive to vandetanib treatment, and suggested that the KIAA1217-RET-fusion gene is a promising target for lung cancer treatment.


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