Research Papers:

Gastrointestinal malignancies harbor actionable MET exon 14 deletions

Jeeyun Lee, Sai-Hong Ignatius Ou, Ji Min Lee, Hee Cheol Kim, Mineui Hong, Sun Young Kim, Jiryeon Jang, Soomin Ahn, So Young Kang, Sujin Lee, Seung Tae Kim, Bogyou Kim, Jaehyun Choi, Kyung-Ah Kim, Jiyun Lee, Charny Park, Se Hoon Park, Joon Oh Park, Ho Yeong Lim, Won Ki Kang, Keunchil Park, Young Suk Park _ and Kyoung-Mee Kim

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Oncotarget. 2015; 6:28211-28222. https://doi.org/10.18632/oncotarget.4721

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Jeeyun Lee1,2,*, Sai-Hong Ignatius Ou3,*, Ji Min Lee4,*, Hee Cheol Kim5,*, Mineui Hong6, Sun Young Kim1, Jiryeon Jang1, Soomin Ahn6, So Young Kang6, Sujin Lee1, Seung Tae Kim1, Bogyou Kim4, Jaehyun Choi4, Kyung-Ah Kim4, Jiyun Lee1, Charny Park1,6, Se Hoon Park1, Joon Oh Park1,2, Ho Yeong Lim1, Won Ki Kang1, Keunchil Park1,2, Young Suk Park1, Kyoung-Mee Kim2,6

1Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

2Innovative Cancer Medicine Institute, Samsung Medical Center, Seoul, Republic of Korea

3Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California, USA

4Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, Yeongtong-gu, Suwon-si, Gyeonggi-do, Korea

5Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

6Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

*These authors have contributed equally to this work

Correspondence to:

Young Suk Park, e-mail: [email protected]

Keunchil Park, e-mail: [email protected]

Kyoung-Mee Kim, e-mail: [email protected]

Keywords: MET exon 14 skipping, colorectal carcinoma, MET monoclonal antibodies, crizotinib, gastrointestinal malignancies

Received: May 19, 2015     Accepted: August 31, 2015     Published: September 10, 2015


Recently, MET exon 14 deletion (METex14del) has been postulated to be one potential mechanism for MET protein overexpression. We screened for the presence of METex14del transcript by multiplexed fusion transcript analysis using nCounter assay followed by confirmation with quantitative reverse transcription PCR with correlation to MET protein expression by immunohistochemistry (IHC) and MET amplification by fluorescence in situ hybridization (FISH). We extracted RNAs from 230 patients enrolled onto the prospective molecular profiling clinical trial (NEXT-1) (NCT02141152) between November 2013 and August 2014. Thirteen METex14del cases were identified including 3 gastric cancer, 4 colon cancer, 5 non-small cell lung cancer, and one adenocarcinoma of unknown primary. Of these 13 METex14del cases, 11 were MET IHC 3+ and 2 were 2+. Only one out of the 13 METex14del cases was MET amplified (MET/CEP ratio > 2.0). Growths of two (gastric, colon) METex14del+ patient tumor derived cell lines were profoundly inhibited by both MET tyrosine kinase inhibitors and a monoclonal antibody targeting MET. In conclusion, METex14del is a unique molecular aberration present in gastrointestinal (GI) malignancies corresponding with overexpression of MET protein but rarely with MET amplification. Substantial growth inhibition of METex14del+ patient tumor derived cell lines by several MET targeting drugs strongly suggests METex14del is a potential actionable driver mutation in GI malignancies.

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