Abstract
Simple SummaryLung cancer has a high incidence and affects both men and women. Targeted therapy options directed at certain mutant proteins, and which avoid systemic chemotherapy are already available and emerging. The gene mesenchymal epithelial transition (MET), encoding a receptor tyrosine kinase protein, is amplified in a subpopulation of lung cancer patients. The aim of our consecutive study was to assess whether next-generation sequencing (NGS) is a reliable method for the detection of MET gene copy number. Our study confirmed that NGS is able to detect cases harboring a high-level MET gene amplification but is unreliable and fails to detect the various levels of MET gene amplification. Therefore, NGS cannot replace the gold standard method of fluorescence in situ hybridization for the detection of MET gene copy number.In non-small cell lung cancer (NSCLC), approximately 1–3% of cases harbor an increased gene copy number (GCN) of the MET gene. This alteration can be due to de novo amplification of the MET gene or can represent a secondary resistance mechanism in response to targeted therapies. To date, the gold standard method to evaluate the GCN of MET is fluorescence in situ hybridization (FISH). However, next-generation sequencing (NGS) is becoming more relevant to optimize therapy by revealing the mutational profile of each NSCLC. Using evaluable n = 205 NSCLC cases of a consecutive cohort, this study addressed the question of whether an amplicon based NGS assay can completely replace the FISH method regarding the classification of MET GCN status. Out of the 205 evaluable cases, only n = 9 cases (43.7%) of n = 16 high-level MET amplified cases assessed by FISH were classified as amplified by NGS. Cases harboring a MET GCN > 10 showed the best concordance when comparing FISH versus NGS (80%). This study confirms that an amplicon-based NGS assessment of the MET GCN detects high-level MET amplified cases harboring a MET GCN > 10 but fails to detect the various facets of MET gene amplification in the context of a therapy-induced resistance mechanism.
Highlights
In solid tumors, driver mutations frequently occur in receptor tyrosine kinases (RTKs) [1]
Of a total of n= 327 samples, n = 205 samples could be analyzed by next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH) for genetic aberrations, including the status of the MET gene copy number (GCN)
Out of n = 327 consecutive non-small cell lung cancer (NSCLC) cases in total, n = 107 cases could not be analyzed via FISH due to an insufficient quality of the fluorescence signal, limited amount of material or lack of the corresponding material (formalin-fixed and paraffin-embedded (FFPE) material from external pathologies)
Summary
Driver mutations frequently occur in receptor tyrosine kinases (RTKs) [1]. In a variety of malignant tumors, the MET gene represents one of the drivers of tumorigenesis due to genetic aberrations, including germline or somatic point mutations, splice-site mutations leading to the skipping of exon 14 (MET exon 14 skipping) or gene amplification [2,4]. The genetic architecture of the MET gene locus is organized in a ladder-like structure characterized by many inverted repeats and resembles an area of common chromosomal fragile sites [5]. These sites are susceptible to genetic aberrations, including gene amplifications. Amplification of the MET gene mainly occurs in lung cancer patients but can develop in adenocarcinomas of the gastroesophageal junction (3.3%) or in glioblastoma (1.7%) [6]
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