Abstract
BackgroundThe aim of this study was to identify critical genes involved in non-small cell lung cancer (NSCLC) pathogenesis that may lead to a more complete understanding of this disease and identify novel molecular targets for use in the development of more effective therapies.MethodsBoth transcriptional and genomic profiling were performed on 69 resected NSCLC specimens and results correlated with mutational analyses and clinical data to identify genetic alterations associated with groups of interest.ResultsCombined analyses identified specific patterns of genetic alteration associated with adenocarcinoma vs. squamous differentiation; KRAS mutation; TP53 mutation, metastatic potential and disease recurrence and survival. Amplification of 3q was associated with mutations in TP53 in adenocarcinoma. A prognostic signature for disease recurrence, reflecting KRAS pathway activation, was validated in an independent test set.ConclusionsThese results may provide the first steps in identifying new predictive biomarkers and targets for novel therapies, thus improving outcomes for patients with this deadly disease.
Highlights
The aim of this study was to identify critical genes involved in non-small cell lung cancer (NSCLC) pathogenesis that may lead to a more complete understanding of this disease and identify novel molecular targets for use in the development of more effective therapies
A key challenge for high-throughput molecular profiling techniques is to distinguish between genes whose expression is altered directly by heritable changes in gene function and those where changes are an inevitable down-stream consequence of primary changes to genes directly involved in disease pathogenesis
After a median follow-up of 36 months (1 - 80) for all patients, 28/68 patients developed recurrent disease, and 23/68 patients died of NSCLC
Summary
The aim of this study was to identify critical genes involved in non-small cell lung cancer (NSCLC) pathogenesis that may lead to a more complete understanding of this disease and identify novel molecular targets for use in the development of more effective therapies. Current treatments offer the potential of cure only to the small number of patients who present with early stage NSCLC, whilst outcomes for those with advanced disease remain poor. As has been the case for other tumour types, molecular profiling techniques have the potential to provide benefit through improved understanding of disease pathogenesis, identification of subgroups in whom current therapies are most likely to be effective and in the development of novel therapies. This study incorporates the results of both transcriptional and genomic profiling for clinically relevant subgroups of NSCLC to identify genes of potential predictive or pathogenic importance in this deadly disease
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