title: Identification of a novel partner gene, KIAA1217, fused to RET: Functional characterization and inhibitor sensitivity of two isoforms in lung adenocarcinoma.
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.
authors.affiliation: Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, Seoul, Korea.|Laboratory of Cancer Genomics and Molecular Pathology, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.
authors.forename: Mi-Sook
authors.initials: MS
authors.lastname: Lee
authors.affiliation: Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Korea.|Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, Korea.
authors.forename: Ryong Nam
authors.initials: RN
authors.lastname: Kim
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Pusan National University School of Medicine, Busan, Korea.|Pusan National University Hospital Biomedical Research Institute, Busan, Korea.
authors.forename: Hoseok
authors.initials: H
authors.lastname: I
authors.affiliation: Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, Seoul, Korea.|Laboratory of Cancer Genomics and Molecular Pathology, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.
authors.forename: Doo-Yi
authors.initials: DY
authors.lastname: Oh
authors.affiliation: Laboratory of Cancer Genomics and Molecular Pathology, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Song
authors.affiliation: Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, Seoul, Korea.|Laboratory of Cancer Genomics and Molecular Pathology, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.
authors.forename: Ka-Won
authors.initials: KW
authors.lastname: Noh
authors.affiliation: Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, Seoul, Korea.|Laboratory of Cancer Genomics and Molecular Pathology, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.
authors.forename: Yu-Jin
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Department of Pathology, Gyeongsang National University School of Medicine, Jinju, Korea.
authors.forename: Jung Wook
authors.initials: JW
authors.lastname: Yang
authors.affiliation: Pfizer Oncology, San Diego, California, USA.
authors.forename: Maruja E
authors.initials: ME
authors.lastname: Lira
authors.affiliation: Department of Pathology, Pusan National University School of Medicine, Busan, Korea.
authors.forename: Chang Hun
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Department of Pulmonology Allergy and Critical Care Medicine, Pusan National University School of Medicine, Busan, Korea.
authors.forename: Min Ki
authors.initials: MK
authors.lastname: Lee
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Pusan National University School of Medicine, Busan, Korea.
authors.forename: Yeoung Dae
authors.initials: YD
authors.lastname: Kim
authors.affiliation: Pfizer Oncology, San Diego, California, USA.|Present address: BGI Genomics, Shenzhen, China.
authors.forename: Mao
authors.initials: M
authors.lastname: Mao
authors.affiliation: Departments of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University College of Medicine, Seoul, Korea.
authors.forename: Joungho
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Thoracic Surgery, Samsung Medical Center, Sungkyunkwan University College of Medicine, Seoul, Korea.
authors.forename: Jhingook
authors.initials: J
authors.lastname: Kim
authors.affiliation: Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, Seoul, Korea.|Laboratory of Cancer Genomics and Molecular Pathology, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.|Departments of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University College of Medicine, Seoul, Korea.
authors.forename: Yoon-La
authors.initials: YL
authors.lastname: Choi
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D041681:NIH 3T3 Cells; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics* / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D014183:Transplantation, Heterologous
chemical_list: C569595:KIAA1217 protein, human; D015514:Oncogene Proteins, Fusion; D010880:Piperidines; D020033:Protein Isoforms; D011506:Proteins; D011799:Quinazolines; D051096:Proto-Oncogene Proteins c-ret; C452423:vandetanib
keywords: KIAA1217; KIAA1217-RET fusion; RET; lung cancer; oncogenic driver