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MET Exon 14 Skipping Mutations in Lung Adenocarcinoma: Clinicopathologic Implications and Prognostic Values  Geun Dong Lee, MD, PhD, Seung Eun Lee, MD,

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Presentation on theme: "MET Exon 14 Skipping Mutations in Lung Adenocarcinoma: Clinicopathologic Implications and Prognostic Values  Geun Dong Lee, MD, PhD, Seung Eun Lee, MD,"— Presentation transcript:

1 MET Exon 14 Skipping Mutations in Lung Adenocarcinoma: Clinicopathologic Implications and Prognostic Values  Geun Dong Lee, MD, PhD, Seung Eun Lee, MD, PhD, Doo-Yi Oh, PhD, Dan-bi Yu, MS, Hae Min Jeong, PhD, Jooseok Kim, BS, Sungyoul Hong, PhD, Hun Soon Jung, PhD, Ensel Oh, PhD, Ji-Young Song, MS, Mi-Sook Lee, PhD, Mingi Kim, BS, Kyungsoo Jung, BS, Jhingook Kim, MD, Young Kee Shin, MD, PhD, Yoon-La Choi, MD, PhD, Hyeong Ryul Kim, MD, PhD  Journal of Thoracic Oncology  Volume 12, Issue 8, Pages (August 2017) DOI: /j.jtho Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

2 Figure 1 Locations of mesenchymal-epithelial transition gene exon 14 skipping (METex14) alterations found in 12 patients with NSCLC. (A) Schematic diagram of METex14 alterations. The position of each METex14 skipping mutation is displayed in relation to the MET gene. Deletion and point mutations are shown in red. The nucleotide position of each mutation is shown on the right. (B) Sanger sequencing histograms of METex14 alterations. Journal of Thoracic Oncology  , DOI: ( /j.jtho ) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

3 Figure 2 Kaplan-Meier survival curves for (A) freedom from recurrence and (B) overall survival based on driver mutations in patients with stages I to IIIA lung adenocarcinoma without preoperative treatment or targeted therapies. Pan-negative indicates negative status for EGFR mutation, anaplastic lymphoma kinase gene (ALK) fusion, ROS1, Ret Proto-Oncogene (RET) fusion, and mesenchymal-epithelial transition gene (MET) exon 14 skipping (METex14). Journal of Thoracic Oncology  , DOI: ( /j.jtho ) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

4 Figure 3 Representative lung adenocarcinomas harboring mesenchymal-epithelial transition gene exon 14 (METex14) skipping mutation of case 2 (A and B) and case 11 (C and D). (A) Histologic features of acinar adenocarcinoma (hematoxylin and eosin staining; original magnification, ×100). (B) Simultaneous membranous and cytoplasmic staining with a score of 2+ in immunohistochemical testing for mesenchymal-epithelial transition protein (original magnification, ×200). (C) Histologic features of solid adenocarcinoma (hematoxylin and eosin staining; original magnification, ×100). (D) Simultaneous membranous and cytoplasmic staining with a score of 3+ in immunohistochemical testing for mesenchymal-epithelial transition protein (original magnification, ×200). Journal of Thoracic Oncology  , DOI: ( /j.jtho ) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

5 Figure 4 Effects of synthetic small interfering RNAs (siRNAs) targeting the junction of mesenchymal-epithelial transition gene exon 14 (METex14) skipping–positive fusion mRNA. (A) Western blotting showing a smaller mesenchymal-epithelial transition (MET) precursor (black arrowhead) in two METex14 skipping–positive cell lines (H596 and Hs746T) than in two cell lines with wild-type (WT) MET (MKN-45 and 293FT). (B) Decreased expression of METex14 skipping–positive fusion mRNA after transfection with two siRNA candidates (1 and 10, with 8 as a negative control) (100 pM) in H596, Hs746T, MKN-45, and 293FT cell lines. Western blot analysis of MET protein, phosphorylated (p) MET (p-MET), AKT, p-AKT, signal transducer and activator of transcription 3 (STAT3), p-STAT3, extracellular signal-regulated kinase (ERK), and p-ERK performed on lysates of H596, Hs746T, MKN-45, and 293FT cell lines. β-actin was used as a loading control. Decreased expression of METex14 skipping–positive fusion mRNA and WT MET after transfection of H596, Hs746T, and MKN-45 cell lines with two siRNA candidates (1 and 10, with 8 as a negative control) (100 pM) for 2 days. Knockdown efficiency was measured quantitatively by qRT-PCR. METex14 skipping–positive fusion mRNA and WT MET expression were normalized to constitutive glucuronidase, beta gene (GUSB) expression. (C) H596, Hs746T, and MKN-45 cells were transfected with two siRNA candidates (1 and 10), and inhibition of proliferation was determined by WST assay. Transfection with siRNA candidate 10 significantly inhibited proliferation of H596 and Hs746T but not MKN-45 cells from day 6 onward. (D) H596 cells were treated with crizotinib (5 μM) and hepatocyte growth factor (HGF) (5 ng/mL) in the presence of nontarget siRNA (Scramble [Sc]) or two siRNA candidates (1 and 10) for 4 days and were determined by WST assay. **p = indicates that significant difference was observed as compared with control groups treated with nontarget siRNA. EXP, exposure; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha. Journal of Thoracic Oncology  , DOI: ( /j.jtho ) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

6 Supplementary Figure 1 Age of the patients with lung adenocarcinoma harboring METex14 skipping compared with patients with EGFR mutation, ALK fusion, ROS1 fusion, RET fusion, and pan-negative (EGFR-/KRAS-/ALK-/ROS1-/RET-/METex14-) lung adenocarcinoma. Journal of Thoracic Oncology  , DOI: ( /j.jtho ) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

7 Supplementary Figure 2 (A) Sanger sequencing histograms of H596 and Hs746 cells. (B) 14 candidates of siRNAs targeting the exon junction for sequence specificity. (C) Three siRNA produced strong, consistent, and reproducible knockdown of the METex14 skipping fusion mRNA. Journal of Thoracic Oncology  , DOI: ( /j.jtho ) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

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