Molecular heterogeneity assessment by next-generation sequencing and response to gefitinib of<i>EGFR</i>mutant advanced lung adenocarcinoma

Bria, Emilio; Pilotto, Sara; Amato, Eliana; Fassan, Matteo; Novello, Silvia; Peretti, Umberto; Vavalà, Tiziana; Kinspergher, Stefania; Righi, Luisella; Santo, Antonio; Brunelli, Matteo; Corbo, Vincenzo; Giglioli, Eliana; Sperduti, Isabella; Milella, Michèle; Chilosi, Marco; Scarpa, Aldo; Tortora, Giampaolo

doi:10.18632/oncotarget.3727

Cited by 61 publications

(60 citation statements)

References 51 publications

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“…This might be clinically relevant, because the presence of additional coexisting mutations in EGFR mutant NSCLC has been reported to be associated with a worse outcome in EGFR mutant patients treated with EGFR TKI [22], although other studies did not find such correlation [23]. Interestingly, in our series 3/4 EGFR mutant patients with progressive disease after EGFR TKI treatment had coexisting mutations in KRAS or BRAF in the primary tumor, in two cases at an allelic frequency higher than EGFR mutations.…”

Section: Discussionmentioning

confidence: 99%

Limits and potential of targeted sequencing analysis of liquid biopsy in patients with lung and colon carcinoma

et al. 2016

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The circulating free tumor DNA (ctDNA) represents an alternative, minimally invasive source of tumor DNA for molecular profiling. Targeted sequencing with next generation sequencing (NGS) can assess hundred mutations starting from a low DNA input. We performed NGS analysis of ctDNA from 44 patients with metastatic non-small-cell lung carcinoma (NSCLC) and 35 patients with metastatic colorectal carcinoma (CRC). NGS detected EGFR mutations in 17/22 plasma samples from EGFR-mutant NSCLC patients (sensitivity 77.3%). The concordance rate between tissue and plasma in NSCLC was much lower for other mutations such as KRAS that, based on the allelic frequency and the fraction of neoplastic cells, were likely to be sub-clonal. NGS also identified EGFR mutations in plasma samples from two patients with EGFR wild type tumor tissue. Both mutations were confirmed by droplet digital PCR (ddPCR) in both plasma and tissue samples. In CRC, the sensitivity of the NGS plasma analysis for RAS mutations was 100% (6/6) in patients that had not resection of the primary tumor before blood drawing, and 46.2% (6/13) in patients with primary tumor resected before enrollment. Our study showed that NGS is a suitable method for plasma testing. However, its clinical sensitivity is significantly affected by the presence of the primary tumor and by the heterogeneity of driver mutations.

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Section: Discussionmentioning

confidence: 99%

Limits and potential of targeted sequencing analysis of liquid biopsy in patients with lung and colon carcinoma

et al. 2016

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“…Secondly, after searching in the PubMed, Embase and the Central Registry of Controlled Trials of the Cochrane Library databases, publication bias remains, since positive results tend to be accepted by journals, whereas negative results are often rejected, or not even submitted. In addition, since p53 mutations occur frequently in the so-called ‘hot-spot’ region of exons 5–8, only the hot-spot will have been examined to evaluate the frequency of TP53 mutations in the majority of studies, whereas meta-analyses have determined that 13.6% of the mutations occur outside exons 5–8 (47–49). Therefore, further studies are warranted to ensure the robustness of the conclusions of the present study.…”

Section: Discussionmentioning

confidence: 99%

TP53 mutation is associated with a poor clinical outcome for non-small cell lung cancer: Evidence from a meta-analysis

Zhou

Huang

et al. 2016

Molecular and Clinical Oncology

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A number of studies have examined the association between tumor protein 53 (TP53) mutations and the clinical outcome in patients with non-small-cell lung cancer (NSCLC), although these have yielded conflicting results. In the present study, electronic databases updated to September 2015 were searched to find relevant studies. A meta-analysis was performed on the eligible studies, which quantitatively evaluated the association between the TP53 mutations and the survival of patients with NSCLC. Subgroup and sensitivity analyses were performed. A total of 19 studies that involved a total of 6,084 patients with NSCLC were included. When the TP53 mutation group (n=1,406) was compared with the wild-type group (lacking TP53 mutations; n=1,965), the wild-type group was associated with a significantly higher overall survival rate [hazard ratio (HR), 1.26; 95% confidence interval (CI) 1.12–1.41, P<0.0001]. Significant benefits of overall survival in the wild-type group were found in the subgroup involving patients with NSCLC in the early stages, including the I/II phases (HR, 1.93, 95% CI, 1.17–3.19, P=0.01; heterogeneity, I2=0.0%, P=0.976) and patients with adenocarcinoma (HR, 3.06; 95% CI, 1.66–5.62, P<0.0001; heterogeneity: I2=0.0%, P=0.976). This meta-analysis has indicated that TP53 gene alteration may be an indicator of a poor prognosis in patients with NSCLC. Furthermore, the results also suggested that the role of TP53 mutations may differ according to different pathological types and clinical stages. The presence of these mutations may define a subset of patients with NSCLC appropriate for investigational therapeutic strategies.

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“…Lung SCC is the second most frequent type of NSCLC after lung AC [5]. In recent years, molecular target therapies for lung AC, including tyrosine kinase inhibitor (gefitinib/erlotinib) against EGFR-sensitive mutants [6,7], crizotinib against ALK fusion [8], and bevacizumab against VEGF over-expression [9], have shown remarkable therapeutic efficacy. However, there is no currently approved molecular target therapy for treatment of lung SCC other than chemotherapy [10–12].…”

Section: Introductionmentioning

confidence: 99%

Identification of Key Transcription Factors Associated with Lung Squamous Cell Carcinoma

Zhang

Chen²,

Wei³

et al. 2017

Med Sci Monit

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BackgroundLung squamous cell carcinoma (lung SCC) is a common type of lung cancer, but its mechanism of pathogenesis is unclear. The aim of this study was to identify key transcription factors in lung SCC and elucidate its mechanism.Material/MethodsSix published microarray datasets of lung SCC were downloaded from Gene Expression Omnibus (GEO) for integrated bioinformatics analysis. Significance analysis of microarrays was used to identify differentially expressed genes (DEGs) between lung SCC and normal controls. The biological functions and signaling pathways of DEGs were mapped in the Gene Otology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database, respectively. A transcription factor gene regulatory network was used to obtain insights into the functions of DEGs.ResultsA total of 1,011 genes, including 539 upregulated genes and 462 downregulated genes, were filtered as DEGs between lung SCC and normal controls. DEGs were significantly enriched in cell cycle, DNA replication, p53 signaling pathway, pathways in cancer, adherens junction, and cell adhesion molecules signaling pathways. There were 57 transcription factors identified, which were used to construct a regulatory network. The network consisted of 736 interactions between 49 transcription factors and 486 DEGs. NFIC, BRCA1, and NFATC2 were the top 3 transcription factors that had the highest connectivity with DEGs and that regulated 83, 82, and 75 DEGs in the network, respectively.ConclusionsNFIC, BRCA1, and NFATC2 might be the key transcription factors in the development of lung SCC by regulating the genes involved in cell cycle and DNA replication pathways.

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Molecular heterogeneity assessment by next-generation sequencing and response to gefitinib ofEGFRmutant advanced lung adenocarcinoma

Cited by 61 publications

References 51 publications

Limits and potential of targeted sequencing analysis of liquid biopsy in patients with lung and colon carcinoma

Limits and potential of targeted sequencing analysis of liquid biopsy in patients with lung and colon carcinoma

TP53 mutation is associated with a poor clinical outcome for non-small cell lung cancer: Evidence from a meta-analysis

Identification of Key Transcription Factors Associated with Lung Squamous Cell Carcinoma

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