Activation of MET by Gene Amplification or by Splice Mutations Deleting the Juxtamembrane Domain in Primary Resected Lung Cancers Ryoichi Onozato, MD,

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Activation of MET by Gene Amplification or by Splice Mutations Deleting the Juxtamembrane Domain in Primary Resected Lung Cancers Ryoichi Onozato, MD, Takayuki Kosaka, MD, Hiroyuki Kuwano, MD, Yoshitaka Sekido, MD, Yasushi Yatabe, MD, Tetsuya Mitsudomi, MD Journal of Thoracic Oncology Volume 4, Issue 1, Pages 5-11 (January 2009) DOI: 10.1097/JTO.0b013e3181913e0e Copyright © 2009 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 Relative copy number of the MET gene determined by real-time quantitative PCR (polymerase chain reaction) in 24 cell lines and 187 lung cancer specimens. MKN45 and NCI-H1993 cell lines showing MET amplification served as positive controls. Solid triangles indicate samples that had MET splice mutations in the following experiments. Journal of Thoracic Oncology 2009 4, 5-11DOI: (10.1097/JTO.0b013e3181913e0e) Copyright © 2009 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 A, Examples of cDNA sequencing chromatograms of the MET gene. In patient T1021, exon 13 was spliced directly to exon 15, skipping exon 14. The chromatogram for the wild type sequence is shown in the upper panel for comparison. Red characters represent a splice mutation. Red arrows indicate the primer position for reverse transcription-polymerase chain reaction (RT-PCR). B, Agarose gel electrophoresis of the RT-PCR product encompassing exon 14 of the MET gene of the paired tumor and normal samples. T, tumor; N, normal lung tissue; N.C, negative control; P.C, positive control. The difference between the larger and smaller bands appears to correspond with length of the exon 14 (141 bp). Journal of Thoracic Oncology 2009 4, 5-11DOI: (10.1097/JTO.0b013e3181913e0e) Copyright © 2009 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 A, Sequencing chromatograms of genomic DNA with intronic mutation of the MET gene: Red characters represent deletions or point mutations in genomic DNA. Four intronic mutations were detected in this analysis. B, Diagrammatic representations of the mechanisms for eliminating exon 14 of the MET gene: (i) The 5′ splice site, 3′ splice site, branch site, and polypyrimidine tract are indicated as consensus motifs at the top of figure.24,25,28 Blue arrows indicated primers for polymerase chain reaction (PCR). (ii) Diagrammatic representations of Figure 3A. (iii) Three intronic mutations reported previously by Kong-Beltran et al.9 All intronic mutations detected in this analysis were different from those reported.9 Each mutation is indicated by a red arrow. Py, pyrimidine. Journal of Thoracic Oncology 2009 4, 5-11DOI: (10.1097/JTO.0b013e3181913e0e) Copyright © 2009 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 Frequencies of MET activation by gene amplification or splice mutation and the mutations of each gene in 211 Japanese patients with lung adenocarcinomas. Thirty percent of the specimens had no mutations of the epidermal growth factor receptor (EGFR), KRAS or HER2 genes and did not show MET activation. Each instance of MET activation detected in this series was mutually exclusionary with these gene mutations. FGFR4 mutation and EML4-ALK fusion gene have been reported to occur in similar exclusionary fashion and be present in 1 of 158 (0.6%) and 5 of 149 (3.4%) of lung adenocarcinomas, respectively, these may be encompassed in the part of Unknown.29,30 Journal of Thoracic Oncology 2009 4, 5-11DOI: (10.1097/JTO.0b013e3181913e0e) Copyright © 2009 International Association for the Study of Lung Cancer Terms and Conditions