MET exon 14 skipping mutation, amplification and overexpression in pulmonary sarcomatoid carcinoma: A multi-center study

Abstract

Background High frequency of MNNG HOS transforming ( MET ) exon 14 skipping mutation ( MET exon 14Δ) has been reported in pulmonary sarcomatoid carcinomas (PSCs). However, the frequencies differ greatly. Our study aims to investigate the frequency of MET alterations and the correlations among MET exon 14Δ, amplification, and protein overexpression in a large cohort of PSCs. MET exon 14Δ, amplification, and protein overexpression were detected in 124 surgically resected PSCs by using Sanger sequencing, fluorescent in situ hybridization (FISH), and immunohistochemistry (IHC) respectively. MET exon 14Δ was identified in 9 (7.3%) of 124 cases, including 6 pleomorphic carcinomas, 2 spindle cell carcinomas and 1 carcinosarcoma. MET amplification and protein overexpression were detected in 6 PSCs (4.8%) and 25 PSCs (20.2%), respectively. MET amplification was significantly associated with overexpression ( P < 0.001). However, MET exon 14Δ has no correlation with MET amplification ( P = 0.370) and overexpression ( P = 0.080). Multivariable analysis demonstrated that pathologic stage (hazard ratio [HR], 2.78; 95% confidence interval [CI], 1.28–6.01; P = 0.010) and MET amplification (HR, 4.71; 95% CI, 1.31–16.98; P = 0.018) were independent prognostic factors for poor median overall survival (mOS). MET alterations including MET exon 14Δ and amplification should be recommended as routine clinical testing in PSCs patients who may benefit from MET inhibitors. MET IHC appears to be an efficient screen tool for MET amplification in PSCs.

Non-Small-Cell Lung Cancer: New Rare Targets—New Targeted Therapies—State of The Art and Future Directions

“…They are most often encountered in smokers and patients diagnosed with lung adenocarcinoma. They should also be routinely sought in patients with pulmonary sarcomatoid carcinoma (PSC), as their prevalence in this patient group exceeds 7% [ 25 ]. In contrast to most driver mutations occurring in lung cancer, they are most commonly observed in elderly patients (after the age of 70) [ 26 ].…”

Mesenchymal-Epithelial Transition Exon 14 Skipping Mutation and Amplification in 5,008 Patients With Lung Cancer

“…Previous studies have shown that the MET exon 14 skipping mutation occurred in approximately 3–5% of lung adenocarcinoma cases, slightly more than 2% of squamous cell carcinomas, and 2.3% of other lung cancer histology types ( 6 , 28 , 29 ). Moreover, the MET exon 14 skipping mutation showed a specifically high incidence in lung sarcomatoid carcinomas (approximately 11–30%) ( 7 , 30 ). In the present study, the MET exon 14 skipping mutation occurred in 0.90% (41/4,564) of adenocarcinoma, 1.02% (3/294) of squamous cell carcinoma, and 8.33% (1/12) of sarcomatoid carcinoma specimens.…”

Detection ofMETexon 14 skipping mutations in non-small cell lung cancer: overview and community perspective

“…In addition, METex14 is not correlated with MET overexpression, whereas mixed results surround the correlation between MET amplification and MET overexpression [7,11,24]. Quantification of MET protein levels by immunohistochemistry has shown that increases in MET levels may be present even in the absence of METex14 or MET amplifications [24,31,42].…”

“…A meta-analysis of patients with NSCLC found that among different histologies, METex14 occurred only in ~1% of squamous cell carcinoma, ~2% of adenocarcinoma, ~6% of adenosquamous cell carcinoma, and ~13% of pulmonary sarcomatoid carcinoma cases [6]. In particular, the prevalence of METex14 in pulmonary sarcomatoid carcinomas can be substantial, ranging between 4.9% and 31.8% [4,6,11,12]. Patients with METex14 NSCLC are significantly older than patients with NSCLC without METex14 as well as those with EGFR, KRAS mutations, or ALK rearrangements.…”

“…It is important to note that MET amplification, which is distinct from METex14, is an additional MET alteration that has been identified as an oncogenic driver associated with poor prognosis [11,23]. Unlike the genetic alterations leading to METex14, MET amplifications are caused by an increased copy number of the MET gene [1,24].…”