Next-Generation Sequencing of Pulmonary Sarcomatoid Carcinoma Reveals High Frequency of Actionable MET Gene Mutations

Abstract

Mutational events of MET leading to exon 14 skipping are frequent and potentially targetable events in PSC.

Molecular characterization of pulmonary sarcomatoid carcinoma: analysis of 33 cases

“…27 KRAS mutations were frequent as well, present in 30% of cases, which is very similar to the rate observed in pulmonary adenocarcinomas Molecular analysis of sarcomatoid carcinoma occurring in the US population, which are usually associated with cigarette smoking. 12 Mutations in KRAS and TP53 have been observed in other studies of pulmonary sarcomatoid carcinoma, 22 a mutation profile closely resembling that of smoking-related lung adenocaricnoma. The genetic similarity between smoking-related adenocarcinoma and sarcomatoid carcinoma is consistent with histopathological observations that many sarcomatoid carcinomas represent a form of high-grade tumor transition from an underlying adenocarcinoma.…”

“…22 We did not identify any MET mutations using the cancer hotspot panel in the current study. To further explore this, a manual review of the raw sequencing data was performed specifically looking for MET alterations, but we did not identify any point mutations/indels within the intron/exon boundary at the 5′ end of exon 14.…”

“…A recent study reported frequent MET exon 14 skipping mutations in pulmonary sarcomatoid carcinomas, which may be targetable, in addition to mutations in other genes without currently available targeted therapy, including TP53 and KRAS. 22,23 The aim of this study is to survey for potentially targetable genetic abnormalities in 33 cases of pulmonary sarcomatoid carcinoma, with the diagnosis previously confirmed based on morphology and immunohistochemistry. 24 …”

MET exon 14 juxtamembrane splicing mutations: clinical and therapeutical perspectives for cancer therapy

“…In comparison with the relative low frequency of detection observed in "classic" lung cancer (numerically comparable to the ALK rearrangement frequency), a strikingly high rate of MET exon 14 skipping mutations, mutually exclusive with other validated driver alterations, was most recently detected in pulmonary sarcomatoid carcinoma (PSC) (22%) (35,52,53). Moreover, an impressive clinico-radiological response was described in a woman affected by an advanced chemotherapy resistant PSC harboring a MET exon 14 skipping mutation, providing further strong proof of the clinical relevance of the findings (35). Similarly, in another series of lung cancer patients, MET exon 14 skipping mutations were identified in 31.8% of the sarcomatoid carcinoma (32).…”

MET/HGF pathway activation as a paradigm of resistance to targeted therapies

“…Mutations that involve the juxtamembrane domain, which is encoded by exons 14 and 15 and is necessary for MET receptor degradation via a critical tyrosine residue (Y1003), can cause tumorigenesis. More recently, recurrent mutations leading to MET exon 14 skipping have been reported to be the most common actionable MET alteration occurring in approximately 3-4% of NSCLCs (26,27) with a higher frequency reported in pulmonary sarcomatoid lung cancer, a rare, very aggressive and treatment-refractory subtype of lung cancer (28).…”