Abstract
Activating and resistance mutations in the tyrosine kinase domain of several oncogenes are frequently associated with non-small cell lung carcinoma (NSCLC). In this study we assessed the frequency, type and abundance of EGFR, KRAS, BRAF, TP53 and ALK mutations in tumour specimens from 184 patients with early and late stage disease using single molecule amplification and re-sequencing technology (SMART). Based on modelling of EGFR mutations, the detection sensitivity of the SMART assay was at least 0.1%. Benchmarking EGFR mutation detection against the gold standard ARMS-PCR assay, SMART assay had a sensitivity and specificity of 98.7% and 99.0%. Amongst the 184 samples, EGFR mutations were the most prevalent (59.9%), followed by KRAS (16.9%), TP53 (12.7%), EML4-ALK fusions (6.3%) and BRAF (4.2%) mutations. The abundance and types of mutations in tumour specimens were extremely heterogeneous, involving either monoclonal (51.6%) or polyclonal (12.6%) mutation events. At the clinical level, although the spectrum of tumour mutation(s) was unique to each patient, the overall patterns in early or advanced stage disease were relatively similar. Based on these findings, we propose that personalized profiling and quantitation of clinically significant oncogenic mutations will allow better classification of patients according to tumour characteristics and provide clinicians with important ancillary information for treatment decision-making.
Highlights
Genetic profiling of tumour specimens from patients with non small-cell lung carcinoma (NSCLC) has identified clinically significant genetic variants in several oncogenes [1,2,3,4]
We propose that personalized profiling and quantitation of clinically significant oncogenic mutations will allow better classification of patients according to tumour characteristics and provide clinicians with important ancillary information for treatment decision-making
We evaluate the performance of a recently developed single allelic molecule counting methodology termed single molecule amplification and resequencing technology (SMART) [34] for the purpose of detecting and quantitating hot spot epithelial growth factor receptor (EGFR), KRAS, BRAF, ALK and TP53 mutations in non-small cell lung carcinoma (NSCLC) tumour specimens and define mutation profiles of early and advanced stage disease
Summary
Genetic profiling of tumour specimens from patients with non small-cell lung carcinoma (NSCLC) has identified clinically significant genetic variants in several oncogenes [1,2,3,4]. 10-50% of tumour biopsies are EGFR mutation positive with L858R and exon 19 deletions in the tyrosine kinase domain accounting for up to 90% of all mutations [7]. Both mutation types result in an increase in constitutive tyrosine kinase activity and are hypersensitive to the reversible action of the small molecule tyrosine kinase inhibitors (TKIs) [8,9,10,11]. Two exon 20 mutations T790M [12, 13] and E20 insertions [14, 15] confer resistance to the action of TKIs on activating mutations by inducing a conformation change that reactivates the tyrosine kinase domain
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