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      An Analysis of EGFR Mutations among 1506 Cases of Non-Small Cell Lung Cancer Patients in Guangxi, China

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          Abstract

          An association between epidermal growth factor receptor (EGFR) and clinical characteristics of non-small cell lung cancer (NSCLC) was reported ten years ago. In addition, a different type of relationship was seen in different ethic races. However, the relationship between these factors is not well understood in the Guangxi province. Up to now, there are only very limited data on the association of TTF1/EGFR protein positivity and EGFR mutation status in NSCLC. This study aims to investigate the role of EGFR gene mutation status on the clinical characteristics and the relationship with TTF-1/EGFR protein positivity of patients with NSCLC in Guangxi, China. 1506 samples from different patients with NSCLC were detected by amplification refractory mutation system for 29 hotspot mutations. Analysis of the relationship between clinical characteristics and EGFR mutation status was performed by using the crosstabs Chi-square and SPSS 21.0 software. Of 1506 samples, 537 (35.7%) revealed tyrosine kinase inhibitor (TKI) sensitive EGFR mutations with 27 (1.8%) cases harboring TKI resistant EGFR mutations or union co-existing EGFR-TKIs sensitive mutations. EGFR-TKIs sensitive mutations were not significantly associated with age and TNM-M stage ( P = 0.863; P = 0.572, respectively). However, they were significantly associated with p-stage, TNM-T stage and TNM-N stage ( P = 0.011, P < 0.001, P = 0.036, respectively). Immunohistochemical studies revealed that TTF-1 and EGFR protein expression level were all associated with EGFR mutation status ( P < 0.001, P = 0.002, respectively). Of the 537 EGFR-TKIs sensitive mutation cases, the rates of exon 19-del, 18 G719X point, exon 21 L858R and L861Q points were 54.6, 0.9, 42.3 and 0.9%, respectively. EGFR TKI-sensitive mutations commonly occur in female, non-smoking and adenocarcinoma patients. The p-stage, TNM-T stage, TNM-N stage, EGFR and TTF-1 protein expression levels have close relationships with EGFR mutation status.

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          Most cited references28

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          Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications.

          Recently it has been reported that mutations in the tyrosine kinase domain of the epidermal growth factor receptor(EGFR) gene occur in a subset of patients with lung cancer showing a dramatic response to EGFR tyrosine kinase inhibitors. To gain further insights in the role of EGFR in lung carcinogenesis, we sequenced exons 18-21 of the tyrosine kinase domain using total RNA extracted from unselected 277 patients with lung cancer who underwent surgical resection and correlated the results with clinical and pathologic features. EGFR mutations were present in 111 patients (40%). Fifty-two were in-frame deletions around codons 746-750 in exon 19, 54 were point mutations including 49 at codon 858 in exon 21 and 4 at codon 719 in exon 18, and 5 were duplications/insertions mainly in exon 20. They were significantly more frequent in female (P < 0.001), adenocarcinomas (P = 0.0013), and in never-smokers (P < 0.001). Multivariate analysis suggested EGFR mutations were independently associated with adenocarcinoma histology (P = 0.0012) and smoking status (P < 0.001), but not with female gender (P = 0.9917). In adenocarcinomas, EGFR mutations were more frequent in well to moderately differentiated tumors (P < 0.001) but were independent of patient age, disease stages, or patient survival. KRAS and TP53 mutations were present in 13 and 41%, respectively. EGFR mutations never occurred in tumors with KRAS mutations, whereas EGFR mutations were independent of TP53 mutations. EGFR mutations define a distinct subset of pulmonary adenocarcinoma without KRAS mutations, which is not caused by tobacco carcinogens.
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            The new lung cancer staging system.

            The International Association for the Study of Lung Cancer (IASLC) has conducted an extensive initiative to inform the revision of the lung cancer staging system. This involved development of an international database along with extensive analysis of a large population of patients and their prognoses. This article reviews the recommendations of the IASLC International Staging Committee for the definitions for the TNM descriptors and the stage grouping in the new non-small cell lung cancer staging system.
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              The relationship between epidermal growth factor receptor mutations and clinicopathologic features in non-small cell lung cancers.

              Recent studies reported that clinical responsiveness to gefitinib was associated with somatic mutation of epidermal growth factor receptor (EGFR) gene in non-small cell lung cancers (NSCLC). Here, we investigated the relationship between EGFR mutation and clinicopathologic features. EGFR mutational status of 120 NSCLCs was determined mainly in EGFR exons 18 to 21 by direct sequence and correlated with clinicopathologic parameters. EGFR mutations were present in 38 cases (32%) and the majority of mutations were in-frame deletions of exon 19 (19 cases) and a missense mutation in exon 21 (18 cases). EGFR mutations were frequently associated with adenocarcinoma (P < 0.0001), never smoker (P < 0.0001), and female gender (P = 0.0001). Of interest, increasing smoke exposure was inversely related to the rate of EGFR mutation (P < 0.0001). Multivariate analysis showed that smoking and histology were independent variables. Furthermore, gender difference was observed for the mutational location (P = 0.01) dominance of exon 19 for males and exon 21 for females. Twenty-one cases were treated with gefitinib and found that EGFR mutation was significantly related to gefitinib responsiveness (P = 0.002). In addition, median survival times of patients with and without EGFR mutations treated with gefitinib were 25.1 and 14.0 months, respectively. Patients with EGFR mutations had approximately 2-fold survival advantage; however, the difference was not significant. We show that EGFR mutations were significantly related to histology and smoke exposure and were a strong predictive factor for gefitinib responsiveness in NSCLC.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                19 December 2016
                2016
                : 11
                : 12
                : e0168795
                Affiliations
                [1 ]Department of Research, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
                [2 ]Department of Thoracic Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
                [3 ]Department of pathology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
                University of Texas MD Anderson Cancer Center, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: LTZ WEW.

                • Data curation: WEW NQM SFN JLL.

                • Formal analysis: WEW HZL.

                • Funding acquisition: LTZ.

                • Investigation: WEW NQM CHW.

                • Methodology: WEW CHW.

                • Project administration: LTZ WEW.

                • Resources: TX NQM LTZ.

                • Software: HZL.

                • Supervision: JHZ YF.

                • Validation: LTZ.

                • Visualization: WEW.

                • Writing – original draft: WEW.

                • Writing – review & editing: WEW LTZ SFN JHZ.

                Article
                PONE-D-16-31024
                10.1371/journal.pone.0168795
                5167423
                27992557
                88a3556b-d8a7-4abc-aa5b-a3152dda7b83
                © 2016 Wei et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 12 August 2016
                : 6 December 2016
                Page count
                Figures: 2, Tables: 5, Pages: 15
                Funding
                Funded by: Guangxi Scientific Research and Technical Development Program
                Award ID: 1298003-2-8
                Award Recipient :
                This study was supported by the Guangxi Scientific Research and Technical Development Program (1298003-2-8).
                Categories
                Research Article
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Carcinomas
                Adenocarcinomas
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Molecular Biology Assays and Analysis Techniques
                Gene Expression and Vector Techniques
                Protein Expression
                Research and Analysis Methods
                Molecular Biology Techniques
                Molecular Biology Assays and Analysis Techniques
                Gene Expression and Vector Techniques
                Protein Expression
                Biology and Life Sciences
                Genetics
                Mutation
                Point Mutation
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Lung and Intrathoracic Tumors
                Non-Small Cell Lung Cancer
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Artificial Gene Amplification and Extension
                Amplification-Refractory Mutation System Analysis
                Research and Analysis Methods
                Molecular Biology Techniques
                Artificial Gene Amplification and Extension
                Amplification-Refractory Mutation System Analysis
                Biology and Life Sciences
                Genetics
                Mutation
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Carcinomas
                Squamous Cell Carcinomas
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Lung and Intrathoracic Tumors
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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