PMID- 26375439
OWN - NLM
STAT- MEDLINE
DCOM- 20160802
LR  - 20191210
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 6
IP  - 29
DP  - 2015 Sep 29
TI  - Gastrointestinal malignancies harbor actionable MET exon 14 deletions.
PG  - 28211-22
LID - 10.18632/oncotarget.4721 [doi]
AB  - 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.
FAU - Lee, Jeeyun
AU  - Lee J
AD  - Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
AD  - Innovative Cancer Medicine Institute, Samsung Medical Center, Seoul, Republic of 
      Korea.
FAU - Ou, Sai-Hong Ignatius
AU  - Ou SH
AD  - Chao Family Comprehensive Cancer Center, University of California Irvine School 
      of Medicine, Orange, California, USA.
FAU - Lee, Ji Min
AU  - Lee JM
AD  - Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology 
      (SAIT)/Samsung Electronics Co. Ltd, Yeongtong-gu, Suwon-si, Gyeonggi-do, Korea.
FAU - Kim, Hee Cheol
AU  - Kim HC
AD  - Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of 
      Medicine, Seoul, Korea.
FAU - Hong, Mineui
AU  - Hong M
AD  - Department of Pathology and Translational Genomics, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
FAU - Kim, Sun Young
AU  - Kim SY
AD  - Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
FAU - Jang, Jiryeon
AU  - Jang J
AD  - Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
FAU - Ahn, Soomin
AU  - Ahn S
AD  - Department of Pathology and Translational Genomics, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
FAU - Kang, So Young
AU  - Kang SY
AD  - Department of Pathology and Translational Genomics, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
FAU - Lee, Sujin
AU  - Lee S
AD  - Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
FAU - Kim, Seung Tae
AU  - Kim ST
AD  - Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
FAU - Kim, Bogyou
AU  - Kim B
AD  - Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology 
      (SAIT)/Samsung Electronics Co. Ltd, Yeongtong-gu, Suwon-si, Gyeonggi-do, Korea.
FAU - Choi, Jaehyun
AU  - Choi J
AD  - Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology 
      (SAIT)/Samsung Electronics Co. Ltd, Yeongtong-gu, Suwon-si, Gyeonggi-do, Korea.
FAU - Kim, Kyung-Ah
AU  - Kim KA
AD  - Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology 
      (SAIT)/Samsung Electronics Co. Ltd, Yeongtong-gu, Suwon-si, Gyeonggi-do, Korea.
FAU - Lee, Jiyun
AU  - Lee J
AD  - Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
FAU - Park, Charny
AU  - Park C
AD  - Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
AD  - Department of Pathology and Translational Genomics, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
FAU - Park, Se Hoon
AU  - Park SH
AD  - Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
FAU - Park, Joon Oh
AU  - Park JO
AD  - Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
AD  - Innovative Cancer Medicine Institute, Samsung Medical Center, Seoul, Republic of 
      Korea.
FAU - Lim, Ho Yeong
AU  - Lim HY
AD  - Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
FAU - Kang, Won Ki
AU  - Kang WK
AD  - Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
FAU - Park, Keunchil
AU  - Park K
AD  - Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
AD  - Innovative Cancer Medicine Institute, Samsung Medical Center, Seoul, Republic of 
      Korea.
FAU - Park, Young Suk
AU  - Park YS
AD  - Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
FAU - Kim, Kyoung-Mee
AU  - Kim KM
AD  - Innovative Cancer Medicine Institute, Samsung Medical Center, Seoul, Republic of 
      Korea.
AD  - Department of Pathology and Translational Genomics, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
RN  - 0 (Anilides)
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyridines)
RN  - 0 (SAIT301)
RN  - 1C39JW444G (cabozantinib)
RN  - EC 2.7.10.1 (MET protein, human)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Amino Acid Sequence
MH  - Anilides/pharmacology
MH  - Antibodies, Monoclonal/pharmacology
MH  - Antibodies, Monoclonal, Humanized
MH  - Cell Proliferation/drug effects/genetics
MH  - DNA Mutational Analysis/methods
MH  - Exons/*genetics
MH  - Female
MH  - Gastrointestinal Neoplasms/*genetics/metabolism/pathology
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - Immunoblotting
MH  - Immunohistochemistry
MH  - In Situ Hybridization, Fluorescence
MH  - Male
MH  - Middle Aged
MH  - Molecular Sequence Data
MH  - Prospective Studies
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Proto-Oncogene Proteins c-met/*genetics/immunology/metabolism
MH  - Pyridines/pharmacology
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - *Sequence Deletion
MH  - Tumor Cells, Cultured
PMC - PMC4695055
OTO - NOTNLM
OT  - MET exon 14 skipping
OT  - MET monoclonal antibodies
OT  - colorectal carcinoma
OT  - crizotinib
OT  - gastrointestinal malignancies
COIS- CONFLICTS OF INTEREST The authors declare no conflicts of interest.
EDAT- 2015/09/17 06:00
MHDA- 2016/08/03 06:00
PMCR- 2015/09/29
CRDT- 2015/09/17 06:00
PHST- 2015/05/19 00:00 [received]
PHST- 2015/08/31 00:00 [accepted]
PHST- 2015/09/17 06:00 [entrez]
PHST- 2015/09/17 06:00 [pubmed]
PHST- 2016/08/03 06:00 [medline]
PHST- 2015/09/29 00:00 [pmc-release]
AID - 4721 [pii]
AID - 10.18632/oncotarget.4721 [doi]
PST - ppublish
SO  - Oncotarget. 2015 Sep 29;6(29):28211-22. doi: 10.18632/oncotarget.4721.