ABSTRACT
The mutations leading to MET exon 14 skipping represent a new class of molecular alterations described in various cancers. These alterations are observed in 2 to 3 % of cases of non-small cell lung cancer (NSCLC). Several cases of NSCLC carrying such alterations and achieving objective response to MET tyrosine kinase inhibitorshave recently been published. This review summarizes the molecular mechanisms responsible for MET exon 14 skipping as well as the consequences of the loss of this exon on receptor activity. We also describe the clinical characteristics of patients with METΔ14 mutations. Finally, we address the issues related to the detection of these mutations in lung cancer, and the need to anticipate resistance to MET inhibitors.
Subject(s)
Carcinoma, Non-Small-Cell Lung/therapy , Lung Neoplasms/therapy , Molecular Targeted Therapy , Mutation , Proto-Oncogene Proteins c-met/genetics , RNA Splice Sites/genetics , Alternative Splicing/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Exons , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Molecular Targeted Therapy/methods , Molecular Targeted Therapy/trends , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-met/antagonists & inhibitorsABSTRACT
INTRODUCTION: Assessment of mutation status in patients with non-small cell lung cancer (NSCLC) is often required. The aim of this study was to confirm the feasibility of molecular mutation analysis in cytologic specimens obtained by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). METHODS: Patients with an EBUS-TBNA positive for adenocarcinoma or NSCLC (squamous cell carcinoma excluded) were included retrospectively from January to December 2010, and prospectively from January to August 2011. Specimens were collected on liquid based preparation and processed on paraffin-embedded cell blocks after ThinPrepÒ procedure. Molecular analysis was performed by a SnaPshot assay for EGFR and by pyrosequencing for KRAS on suitable samples (>5% tumor cells). RESULTS: Eighty-two patients were included (63 adenocarcinoma). Molecular analysis for EGFR was feasible in 80 (97.6%) patients and for KRAS in 78 (95.1%) patients. Molecular analysis identified EGFR and KRAS mutations in tumor samples from four (5%) and 18 (23%) patients respectively. All EGFR mutations were found in women. CONCLUSIONS: Molecular analysis mutations can be performed routinely in cytologic specimens obtained by EBUS-TBNA.
Subject(s)
Bronchoscopy/methods , Carcinoma, Non-Small-Cell Lung/pathology , DNA Mutational Analysis/methods , Endoscopic Ultrasound-Guided Fine Needle Aspiration/methods , ErbB Receptors/genetics , Lung Neoplasms/pathology , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Adenocarcinoma of Lung , Aged , Carcinoma, Non-Small-Cell Lung/genetics , Female , Humans , Lung Neoplasms/genetics , Male , Middle Aged , Mutation, Missense , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins p21(ras) , Retrospective Studies , Specimen Handling/methods , ras Proteins/geneticsABSTRACT
BACKGROUND: Microsatellite instability (MSI) is a molecular phenotype due to defective DNA mismatch repair (MMR) system. It is used to predict outcome of colorectal tumours and to screen tumours for Lynch syndrome (LS). A pentaplex panel composed of five mononucleotide markers has been largely recommended for determination of the MSI status. However, its sensitivity may be taken in default in occasional situations. The aim of the study was to optimise this panel for the detection of MSI. METHODS: We developed an assay allowing co-amplification of six mononucleotide repeat markers (BAT25, BAT26, BAT40, NR21, NR22, NR27) and one polymorphic dinucleotide marker (D3S1260) in a single reaction. Performances of the new panel were evaluated on a cohort of patients suspected of LS. RESULTS: We demonstrate that our assay is technically as easy to use as the pentaplex assay. The hexaplex panel shows similar performances for the identification of colorectal and non-MSH6-deficient tumours. On the other hand, the hexaplex panel has higher sensitivity for the identification of MSH6-deficient tumours (94.7% vs 84.2%) and MMR-deficient tumours other than colorectal cancer (92.9% vs 85.7%). CONCLUSION: The hexaplex panel could thus be an attractive alternative to the pentaplex panel for the identification of patients with LS.
