Comprehensive Molecular Characterization of Young Chinese Patients with Lung Adenocarcinoma Identified a Distinctive Genetic Profile

Hou, Helei; Zhu, Hua; Zhao, Han; Yan, Wei‐Hua; Wang, Yongjie; Jiang, Man; Liu, Bin; Liu, Dong; Zhou, Na; Zhang, Chuantao; Li, Pansong; Chang, Lianpeng; Guan, Yanfang; Wang, Zhe; Zhang, Xiaoping; Li, Zhuokun; Fang, Bingliang; Zhang, Xiaochun

doi:10.1634/theoncologist.2017-0629

Cited by 41 publications

(73 citation statements)

References 28 publications

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“…However, other studies revealed that the second‐generation TKI afatinib was more active in patients with NSCLC who harbored certain types of uncommon EGFR mutations, especially G719, L861Q, and S768I , which indicated that accurate detection of uncommon EGFR mutations would help patients with NSCLC to select targeted therapeutic drugs more precisely. Besides, it was noteworthy that comutation of EGFR and TP53 was frequently found in female patients in this study; another study showed that it was more likely to occur in young patients <45 years of age . At the same time, the common mutation of EGFR and TP53 is correlated with a poor prognosis .…”

Section: Discussionmentioning

confidence: 51%

“…We used 900× depth sequencing and found a total of 56 different types of uncommon EGFR mutations, which could be observed in the extracellular domain (12.3%), transmembrane domain (1.9%), exon 18 (nucleotide‐binding loop, 35.7%), exon 19 (4.5%), exon 20 (16.2%), exon 21 (activation loop, 20.1%), autophosphorylation domain (5.8%), and structure variations (3.2%). Some uncommon EGFR mutations with high incidence (more than 10 cases) included L861 M/Q/R, G719A/C/S, S768I, and E709A/K, which have been described previously . L861Q, G719X, and S768I were EGFR mutations with weak activities; the median PFS of patients who received EGFR TKIs as first‐line treatment was 7.6 months, 8.2 months, and 3.4 months, respectively, which was significantly shorter than that in patients with common EGFR mutations (exon 19 deletion and L858R) .…”

Section: Discussionmentioning

confidence: 77%

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Genomic Signature of Driver Genes Identified by Target Next-Generation Sequencing in Chinese Non-Small Cell Lung Cancer

Dai

Wang

et al. 2019

The Oncologist

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Background Non‐small cell lung cancer (NSCLC) is one of the most common human malignancies and the leading cause of cancer‐related death. Over the past few decades, genomic alterations of cancer driver genes have been identified in NSCLC, and molecular testing and targeted therapies have become standard care for lung cancer patients. Here we studied the unique genomic profile of driver genes in Chinese patients with NSCLC by next‐generation sequencing (NGS) assay. Materials and Methods A total of 1,200 Chinese patients with NSCLC were enrolled in this study. The median age was 60 years (range: 26–89), and 83% cases were adenocarcinoma. NGS‐based genomic profiling of major lung cancer‐related genes was performed on formalin‐fixed paraffin‐embedded tumor samples and matched blood. Results Approximately 73.9% of patients with NSCLC harbored at least one actionable alteration recommended by the National Comprehensive Cancer Network guideline, including epidermal growth factor receptor (EGFR), ALK, ERBB2, MET, BRAF, RET, and ROS1. Twenty‐seven patients (2.2%) harbored inherited germline mutations of cancer susceptibility genes. The frequencies of EGFR genomic alterations (both mutations and amplification) and ALK rearrangement were identified as 50.1% and 7.8% in Chinese NSCLC populations, respectively, and significantly higher than the Western population. Fifty‐six distinct uncommon EGFR mutations other than L858R, exon19del, exon20ins, or T790M were identified in 18.9% of patients with EGFR‐mutant NSCLC. About 7.4% of patients harbored both sensitizing and uncommon mutations, and 11.6% of patients harbored only uncommon EGFR mutations. The uncommon EGFR mutations more frequently combined with the genomic alterations of ALK, CDKN2A, NTRK3, TSC2, and KRAS. In patients <40 years of age, the ALK‐positive percentage was up to 28.2%. Moreover, 3.2% of ALK‐positive patients harbored multi ALK rearrangements, and seven new partner genes were identified. Conclusion More unique features of cancer driver genes in Chinese NSCLC were identified by next‐generation sequencing. These findings highlighted that NGS technology is more feasible and necessary than other molecular testing methods, and suggested that the special strategies are needed for drug development and targeted therapy for Chinese patients with NSCLC. Implications for Practice Molecular targeted therapy is now the standard first‐line treatment for patients with advanced non‐small cell lung cancer (NSCLC). Samples of 1,200 Chinese patients with NSCLC were analyzed through next‐generation sequencing to characterize the unique feature of uncommon EGFR mutations and ALK fusion. The results showed that 7.4% of EGFR‐mutant patients harbored both sensitizing and uncommon mutations and 11.6% harbored only uncommon mutations. Uncommon EGFR mutations more frequently combined with the genomic alterations of ALK, CDKN2A, NTRK3, TSC2, and KRAS. ALK fusion was more common in younger patients, and the frequency decreased monotonically with age. 3.2% of ALK‐positive patien...

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Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 77%

Genomic Signature of Driver Genes Identified by Target Next-Generation Sequencing in Chinese Non-Small Cell Lung Cancer

Dai

Wang

et al. 2019

The Oncologist

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“…According to previous studies, TP53 mutations could be found in 30%-72% of all EGFR-mutated NSCLCs and 25%-56% of ALK-positive NSCLCs, predominantly in smokers [26,27] and the younger patients [28] , but were rare in patients with other less common targeted mutations like KRAS mutation/ROS1 re-arrangement/RET re-arrangement [29]. Previous studies have suggested that TP53 concurrent mutation might adversely impact the survival of patients with advanced NSCLC treated with EGFR-TKIs or ALK-TKIs for oncogenic EGFR or ALK mutations [30][31][32][33].…”

Section: Introductionmentioning

confidence: 90%

Prognostic value of TP53 concurrent mutations for EGFR- TKIs and ALK-TKIs based targeted therapy in advanced non-small cell lung cancer: a meta-analysis

Qin

Hou

et al. 2019

Preprint

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Background The prognostic significance of TP53 concurrent mutations in patients with epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)- mutated advanced non–small-cell lung cancer (NSCLC) who received EGFR-tyrosine kinase inhibitors (TKIs) or ALK-TKIs based targeted therapy remains controversial. Therefore, the present meta-analysis was performed to investigate the association between TP53 concurrent mutations and prognosis of patients with advanced NSCLC undergoing EGFR-TKIs or ALK-TKIs treatments. Methods Eligible studies were identified by searching the online databases PubMed, Embase, Medline, The Cochrane library and Web of Science. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to clarify the correlation between TP53 mutation status and prognosis of patients. This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Results In total, 15 studies with 1342 patients were included for final analysis. Overall, concurrent TP53 mutation was associated with unfavorable progression-free survival (PFS) (HR=1.88, 95%CI: 1.59-2.23, p<0.001, I2=0.0%, P=0.792) and overall survival (OS) (HR=1.92, 95%CI: 1.55-2.38, p<0.001, I2=0.0%, P=0.515). Subgroup analysis based on type of targeted therapy (EGFR-TKIs or ALK-TKIs, pathological type of cancer (adenocarcinoma only or all NSCLC subtypes) and line of treatment (first-line only or all lines) all showed that TP53 mutations was associated with shorter survivals of patients with EGFR-TKIs or ALK-TKIs treatments. Particularly, in patients with first-line EGFR-TKIs treatment, significantly poorer prognosis was observed in patients with TP53 concurrent mutations (pooled HR for PFS: 1.69, 95% CI 1.25-2.27, P<0.001, I2=0.0%, P=0.473; pooled HR for OS: 1.94, 95% CI 1.36-2.76, P<0.001, I2=0.0%, P=0.484). Begg’s funnel plots and Egger’s tests indicated no significant publication bias in this study. Conclusions This meta-analysis indicated that concurrent TP53 mutations was a negative prognostic factor and associated with poorer outcomes of patients with EGFR-TKIs or ALK-TKIs treatments in advanced NSCLC. In addition, our study provided evidence that TP53 mutations might be involved in primary resistance to EGFR-TKIs treatments in patients with sensitive EGFR mutations in advanced NSCLC.

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“…Meanwhile, over-activation of the ALK signaling such as ALK amplification, up-regulation of bypass signaling pathways might be chief culprits that confer primary resistance to ALK-TKIs [20,21].In NSCLC, TP53 mutations are the most common co-occurring events with driver oncogenes. According to previous studies, TP53 mutations could be found in 30%-72% of all EGFR-mutated NSCLCs and 25%-56% of ALK-positive NSCLCs, predominantly in smokers [23,24] and the younger patients [25] , but were rare in patients with other less common targeted mutations like KRAS mutation/ROS1 rearrangement/RET re-arrangement [26].…”

Section: Nsclcmentioning

confidence: 94%

Prognostic value of TP53 concurrent mutations for EGFR- TKIs and ALK-TKIs based targeted therapy in advanced non-small cell lung cancer: a meta-analysis

Qin

Hou

et al. 2020

Preprint

Self Cite

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Background The prognostic significance of TP53 concurrent mutations in patients with epidermal growth factor receptor (EGFR)-or anaplastic lymphoma kinase (ALK)-mutated advanced non-smallcell lung cancer (NSCLC) who received EGFR-tyrosine kinase inhibitors (TKIs) or ALK-TKIs based targeted therapy remains controversial. Therefore, the present meta-analysis was performed to investigate the association between TP53 concurrent mutations and prognosis of patients with advanced NSCLC undergoing EGFR-TKIs or ALK-TKIs treatments.Methods Eligible studies were identified by searching the online databases PubMed, Embase, Medline,The Cochrane library and Web of Science. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to clarify the correlation between TP53 mutation status and prognosis of patients.This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. ResultsIn total, 15 studies with 1342 patients were included for final analysis. Overall, concurrent TP53 mutation was associated with unfavorable progression-free survival (PFS) (HR=1.88, 95%CI:1.59-2.23, p<0.001, I2=0.0%, P=0.792) and overall survival (OS) (HR=1.92, 95%CI: 1.55-2.38, p<0.001, I2=0.0%, P=0.515). Subgroup analysis based on type of targeted therapy (EGFR-TKIs or ALK-TKIs, pathological type of cancer (adenocarcinoma only or all NSCLC subtypes) and line of treatment (first-line only or all lines) all showed that TP53 mutations was associated with shorter survivals of patients with EGFR-TKIs or ALK-TKIs treatments. Particularly, in patients with first-line EGFR-TKIs treatment, significantly poorer prognosis was observed in patients with TP53 concurrent mutations (pooled HR for PFS: 1.69, 95% CI 1.25-2.27, P<0.001, I2=0.0%, P=0.473; pooled HR for OS:1.94, 95% CI 1.36-2.76, P<0.001, I2=0.0%, P=0.484). Begg's funnel plots and Egger's tests indicated no significant publication bias in this study.Conclusions This meta-analysis indicated that concurrent TP53 mutations was a negative prognostic factor and associated with poorer outcomes of patients with EGFR-TKIs or ALK-TKIs treatments in advanced NSCLC. In addition, our study provided evidence that TP53 mutations might be involved in primary resistance to EGFR-TKIs treatments in patients with sensitive EGFR mutations in advanced

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Comprehensive Molecular Characterization of Young Chinese Patients with Lung Adenocarcinoma Identified a Distinctive Genetic Profile

Cited by 41 publications

References 28 publications

Genomic Signature of Driver Genes Identified by Target Next-Generation Sequencing in Chinese Non-Small Cell Lung Cancer

Genomic Signature of Driver Genes Identified by Target Next-Generation Sequencing in Chinese Non-Small Cell Lung Cancer

Prognostic value of TP53 concurrent mutations for EGFR- TKIs and ALK-TKIs based targeted therapy in advanced non-small cell lung cancer: a meta-analysis

Prognostic value of TP53 concurrent mutations for EGFR- TKIs and ALK-TKIs based targeted therapy in advanced non-small cell lung cancer: a meta-analysis

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