2. Academic Validation
  3. MET Exon 14 Skipping Mutations in Lung Adenocarcinoma: Clinicopathologic Implications and Prognostic Values

MET Exon 14 Skipping Mutations in Lung Adenocarcinoma: Clinicopathologic Implications and Prognostic Values

  • J Thorac Oncol. 2017 Aug;12(8):1233-1246. doi: 10.1016/j.jtho.2017.04.031.
Geun Dong Lee 1,  Seung Eun Lee 2,  Doo-Yi Oh 3,  Dan-Bi Yu 3,  Hae Min Jeong 4,  Jooseok Kim 4,  Sungyoul Hong 5,  Hun Soon Jung 6,  Ensel Oh 7,  Ji-Young Song 7,  Mi-Sook Lee 3,  Mingi Kim 3,  Kyungsoo Jung 3,  Jhingook Kim 8,  Young Kee Shin 9,  Yoon-La Choi 10,  Hyeong Ryul Kim 1
Affiliations

Affiliations

  • 1 Department of Thoracic and Cardiovascular Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
  • 2 Department of Pathology, Konkuk University School of Medicine, Konkuk University Medical Center, Seoul, Republic of Korea.
  • 3 Laboratory of Cancer Genomics and Molecular Pathology, Samsung Medical Center, Seoul, Republic of Korea; Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Republic of Korea.
  • 4 Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
  • 5 Research Institute for Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
  • 6 ABION, Inc., R&D Center, Seoul, Republic of Korea.
  • 7 Laboratory of Cancer Genomics and Molecular Pathology, Samsung Medical Center, Seoul, Republic of Korea.
  • 8 Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
  • 9 Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Republic of Korea; Research Institute for Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
  • 10 Laboratory of Cancer Genomics and Molecular Pathology, Samsung Medical Center, Seoul, Republic of Korea; Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Republic of Korea; Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Electronic address: ylachoi@skku.edu.
PMID: 28502721 DOI: 10.1016/j.jtho.2017.04.031
Abstract

Introduction: Response to mesenchymal-epithelial transition (MET) inhibitors in NSCLC with mesenchymal-epithelial transition gene (MET) exon 14 skipping (METex14) has fueled molecular screening efforts and the search for optimal therapies. However, further work is needed to refine the clinicopathologic and prognostic implications of METex14 skipping.

Methods: Among 795 East Asian patients who underwent a surgical procedure for NSCLC, we screened 45 patients with quintuple-negative (EGFR-negative/KRAS-negative/anaplastic lymphoma kinase gene [ALK]-negative/ROS1-negative/RET proto-oncogene [RET]-negative) lung adenocarcinomas by using reverse-transcriptase polymerase chain reaction and found 17 patients (37.8%) with METex14 skipping. We also investigated the effect of small interfering RNA (siRNA) targeting skipping junction in cells with METex14 skipping.

Results: The median age of the 17 patients was 73 years. The acinar subtype was predominant (52.9%), followed by the solid subtype (35.3%). MET immunohistochemistry demonstrated 100% sensitivity and 70.4% specificity. Multivariate analyses showed that patients with METex14 skipping had a higher recurrence rate than those with ALK fusion (versus METex14 skipping) (hazard ratio = 0.283, 95% confidence interval: 0.119-0.670) in stage I to IIIA disease; however, the differences in overall survival were not significant after adjustment for pathologic stage (p = 0.669). Meanwhile, siRNA decreased MET-driven signaling pathways in Hs746T cells, and combined treatment with siRNA and crizotinib inhibited cell proliferation in crizotinib-resistant H596 cells.

Conclusions: The prevalence of METex14 skipping was quite high in East Asian patients without Other driver mutations in lung adenocarcinomas. METex14 skipping was associated with old age, the acinar or solid histologic subtype, and high MET immunohistochemical expression. The prognosis of patients with METex14 skipping was similar to that of patients with major driver mutations. siRNA targeting the junction of METex14 skipping could inhibit MET-driven signaling pathways in cells with METex14 skipping.

Keywords

Lung adenocarcinoma; MET exon 14 skipping; MET inhibitor; siRNA.

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