Comprehensive investigation of oncogenic driver mutations in Chinese non-small cell lung cancer patients.

Rui Wang,Yihua Sun,Deng Cai,Ting Ye,Yang Zhang,Yunjian Pan,Hang Li,Yiliang Zhang,Haichuan Hu,Xiaoyang Luo,Yuan Li,Bin Li,Lei Shen,Haiquan Chen

doi:10.18632/oncotarget.5549

Abstract

To determine the frequency of driver mutations in Chinese non-small cell lung cancer (NSCLC) patients. Comprehensive mutational analysis was performed in 1356 lung adenocarcinoma, 503 squamous cell carcinoma, 57 adenosquamous lung carcinoma, 19 large cell carcinoma and 8 sarcomatoid carcinoma. The effect of EGFR tyrosine kinase inhibitors (TKIs) on EGFR-mutated lung adenocarcinoma patients after disease recurrence was investigated. Mutations in EGFR kinase domain, HER2 kinase domain, KRAS, BRAF, ALK, ROS1 and RET were mutually exclusive. In lung adenocarcinoma cases "pan-negative" for the seven above-mentioned driver mutations, we also detected two oncogenic EGFR extracellular domain mutations (A289D and R324L), two HER2 extracellular and transmembrane domain mutations (S310Y and V659E), one ARAF S214C mutation and two CD74-NRG1 fusions. Six (1.2%) FGFR3 activating mutations were identified in lung squamous cell carcinoma (five S249C and one R248C). There were three (15.8%) EGFR mutations and four (21.1%) KRAS mutations in large cell carcinoma. Three (37.5%) KRAS mutations were detected in sarcomatoid carcinoma. In EGFR-mutated lung adenocarcinoma patients who experienced disease recurrence, treatment with EGFR TKIs was an independent predictor of better overall survival (HR = 0.299, 95% CI: 0.172-0.519, P < 0.001). We determined the frequency of driver mutations in a large series of Chinese NSCLC patients. EGFR TKIs might improve the survival outcomes of EGFR-mutated lung adenocarcinoma patients who experienced disease recurrence.

Highlights

Treatment strategies for non-small cell lung cancer (NSCLC) have been revolutionized since the identification of EGFR activating mutations which predict response to EGFR tyrosine kinase inhibitors (TKIs) in 2004 [1, 2]
Various oncogenic driver mutations have been identified in NSCLC, which enables this disease to be classified into clinically relevant molecular subgroups
A total of 1356 lung adenocarcinoma cases from April 2007 to May 2013 were sequenced for EGFR kinase domain mutations, KRAS mutations, HER2 kinase domain mutations, BRAF mutations, ALK fusions, ROS1 fusions, RET fusions and AKT1 mutations

Summary

Introduction

Treatment strategies for non-small cell lung cancer (NSCLC) have been revolutionized since the identification of EGFR activating mutations which predict response to EGFR tyrosine kinase inhibitors (TKIs) in 2004 [1, 2]. Various oncogenic driver mutations have been identified in NSCLC, which enables this disease to be classified into clinically relevant molecular subgroups. Large phase III randomized clinical trials have proved the efficacy of targeted therapies over conventional cytotoxic chemotherapy for NSCLC patients harboring EGFR mutations [3,4,5,6] or ALK fusions [7]. We presented our sequencing results of a comprehensive www.impactjournals.com/oncotarget panel of oncogenic driver mutations in a large prospective series of NSCLC patients who received surgical resection

Methods

Results

Conclusion