Next-generation sequencing of pulmonary sarcomatoid carcinoma reveals high frequency of actionable MET gene mutations

Xuewen Liu, Yuxia Jia, Mark B. Stoopler, Yufeng Shen, Haiying Cheng, Jinli Chen, Mahesh Mansukhani, Sanjay Koul, Balazs Halmos, Alain C. Borczuk

Research output: Contribution to journalArticle

149 Scopus citations

Abstract

Purpose: To further understand the molecular pathogenesis of pulmonary sarcomatoid carcinoma (PSC) and develop new therapeutic strategies in this treatment-refractory disease. Materials and Methods: Whole-exome sequencing in a discovery set (n510) as well as targetedMET mutation screening in an independent validation set (n = 26) of PSC were performed. Reverse transcriptase polymerase chain reaction and Western blotting were performed to validate MET exon 14 skipping. Functional studies for validation of the oncogenic roles of MET exon 14 skippingwere conducted in lung adenosquamous cell line H596 (MET exon 14 skipped and PIK3CA mutated) and gastric adenocarcinoma cell line Hs746T (MET exon 14 skipped). Response to MET inhibitor therapy with crizotinib in a patient with advanced PSC and MET exon 14 skipping was evaluated to assess clinical translatability. Results: In addition to confirming mutations in known cancer-associated genes (TP53, KRAS, PIK3CA, MET, NOTCH, STK11, and RB1), several novel mutations in additional genes, including RASA1, CDH4, CDH7, LAMB4, SCAF1, and LMTK2, were identified and validated. MET mutations leading to exon 14 skipping were identified in eight (22%) of 36 patient cases; one of these tumors also harbored a concurrent PIK3CA mutation. Short interfering RNA silencing of MET and MET inhibition with crizotinib showed marked effects on cell viability and decrease in downstream AKT and mitogen-activated protein kinase activation in Hs746T and H596 cells. Concurrent PIK3CA mutation required addition of a second agent for successful pathway suppression and cell viability effect. Dramatic response to crizotinib was noted in a patient with advanced chemotherapy-refractory PSC carrying a MET exon 14 skipping mutation. Conclusion: Mutational events of MET leading to exon 14 skipping are frequent and potentially targetable events in PSC.

Original languageEnglish (US)
Pages (from-to)794-802
Number of pages9
JournalJournal of Clinical Oncology
Volume34
Issue number8
DOIs
StatePublished - Mar 10 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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