Dataset Information

Mutational analysis of EGFR and related signaling pathway genes in lung adenocarcinomas identifies a novel somatic kinase domain mutation in FGFR4.

ABSTRACT: Fifty percent of lung adenocarcinomas harbor somatic mutations in six genes that encode proteins in the EGFR signaling pathway, i.e., EGFR, HER2/ERBB2, HER4/ERBB4, PIK3CA, BRAF, and KRAS. We performed mutational profiling of a large cohort of lung adenocarcinomas to uncover other potential somatic mutations in genes of this signaling pathway that could contribute to lung tumorigenesis.We analyzed genomic DNA from a total of 261 resected, clinically annotated non-small cell lung cancer (NSCLC) specimens. The coding sequences of 39 genes were screened for somatic mutations via high-throughput dideoxynucleotide sequencing of PCR-amplified gene products. Mutations were considered to be somatic only if they were found in an independent tumor-derived PCR product but not in matched normal tissue. Sequencing of 9MB of tumor sequence identified 239 putative genetic variants. We further examined 22 variants found in RAS family genes and 135 variants localized to exons encoding the kinase domain of respective proteins. We identified a total of 37 non-synonymous somatic mutations; 36 were found collectively in EGFR, KRAS, BRAF, and PIK3CA. One somatic mutation was a previously unreported mutation in the kinase domain (exon 16) of FGFR4 (Glu681Lys), identified in 1 of 158 tumors. The FGFR4 mutation is analogous to a reported tumor-specific somatic mutation in ERBB2 and is located in the same exon as a previously reported kinase domain mutation in FGFR4 (Pro712Thr) in a lung adenocarcinoma cell line.This study is one of the first comprehensive mutational analyses of major genes in a specific signaling pathway in a sizeable cohort of lung adenocarcinomas. Our results suggest the majority of gain-of-function mutations within kinase genes in the EGFR signaling pathway have already been identified. Our findings also implicate FGFR4 in the pathogenesis of a subset of lung adenocarcinomas.

SUBMITTER: Marks JL

PROVIDER: S-EPMC1855985 | biostudies-literature | 2007 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Mutational analysis of EGFR and related signaling pathway genes in lung adenocarcinomas identifies a novel somatic kinase domain mutation in FGFR4.

Marks Jenifer L JL McLellan Michael D MD Zakowski Maureen F MF Lash Alex E AE Kasai Yumi Y Broderick Stephen S Sarkaria Inderpal S IS Pham Duykhanh D Singh Bhuvanesh B Miner Tracie L TL Fewell Ginger A GA Fulton Lucinda L LL Mardis Elaine R ER Wilson Richard K RK Kris Mark G MG Rusch Valerie W VW Varmus Harold H Pao William W

PloS one 20070509 5

<h4>Background</h4>Fifty percent of lung adenocarcinomas harbor somatic mutations in six genes that encode proteins in the EGFR signaling pathway, i.e., EGFR, HER2/ERBB2, HER4/ERBB4, PIK3CA, BRAF, and KRAS. We performed mutational profiling of a large cohort of lung adenocarcinomas to uncover other potential somatic mutations in genes of this signaling pathway that could contribute to lung tumorigenesis.<h4>Methodology/principal findings</h4>We analyzed genomic DNA from a total of 261 resected, ...[more]

PMID: 17487277

Similar Datasets

Project description:BackgroundA subset of lung adenocarcinoma with EGFR-tyrosine kinase inhibitor sensitizing mutations (mEGFR) is common in non-smokers and women, suggesting that mutational stressors other than smoking are involved.MethodsTargeted sequencing using a custom panel containing 70 cancer-related genes were performed from 73 cases of lung adenocarcinoma with mEGFR (study cohort). In parallel, publicly available data of 47 TCGA-LUAD cases with mEGFR (LUAD cohort) were extracted from the GDC data portal and analyzed by non-negative matrix factorization using the Maftools package.ResultsIn the study cohort, the C?>?A transversions accounted for 12.9% of all single nucleotide variations (SNVs), comprising the second smallest proportion among SNVs. The E19del-subgroup had a significantly lower mutational burden with significantly higher Ti/Tv ratio than the SNV-subgroup, which includes cases with L858R and other EGFR-TKI sensitizing SNVs. (P?=?0.0326 and 0.0002, respectively, Mann-Whitney U test). In the LUAD cohort, the mutational burden was substantially lower than in other TCGA cancer cohorts, and the frequency of C?>?A transversions was 30.3%, occupying the second frequency. The E19del-subgroup had a lower mutational burden overall and a higher Ti/Tv ratio than the SNV-subgroup (P?=?0.0497 and P?=?0.0055, respectively, Mann-Whitney U test). Smoking-related signature 4 was observed only in the L858R-subgroup, while ignature 30 and 5 was observed in both groups.ConclusionsLung adenocarcinoma with mEGFR(+) has a lower mutational burden and does not show a characteristic mutation pattern influenced by smoking. E19del and L858R, which are representative subtypes of mEGFR(+) lung adenocarcinoma, differ in terms of mutational spectrum, as the E19del-subgroup has a lower mutation burden and a higher Ti/Tv ratio than the SNV-subgroup. These findings could help explain the differences in the responses to EGFR-TKIs and in the clinical courses between the two lung adenocarcinoma subgroups.

Project description:BackgroundMutations in the epidermal growth factor receptor (EGFR) gene are associated with increased sensitivity of lung cancers to kinase inhibitors like erlotinib. Mechanisms of cell death that occur after kinase inhibition in these oncogene-dependent tumors have not been well delineated. We sought to improve understanding of this process in order to provide insight into mechanisms of sensitivity and/or resistance to tyrosine kinase inhibitors and to uncover new targets for therapy.Methods and findingsUsing a panel of human lung cancer cell lines that harbor EGFR mutations and a variety of biochemical, molecular, and cellular techniques, we show that EGFR kinase inhibition in drug-sensitive cells provokes apoptosis via the intrinsic pathway of caspase activation. The process requires induction of the proapoptotic BH3-only BCL2 family member BIM (i.e., BCL2-like 11, or BCL2L11); erlotinib dramatically induces BIM levels in sensitive but not in resistant cell lines, and knockdown of BIM expression by RNA interference virtually eliminates drug-induced cell killing in vitro. BIM status is regulated at both transcriptional and posttranscriptional levels and is influenced by the extracellular signal-regulated kinase (ERK) signaling cascade downstream of EGFR. Consistent with these findings, lung tumors and xenografts from mice bearing mutant EGFR-dependent lung adenocarcinomas display increased concentrations of Bim after erlotinib treatment. Moreover, an inhibitor of antiapoptotic proteins, ABT-737, enhances erlotinib-induced cell death in vitro.ConclusionsIn drug-sensitive EGFR mutant lung cancer cells, induction of BIM is essential for apoptosis triggered by EGFR kinase inhibitors. This finding implies that the intrinsic pathway of caspase activation may influence sensitivity and/or resistance of EGFR mutant lung tumor cells to EGFR kinase inhibition. Manipulation of the intrinsic pathway could be a therapeutic strategy to enhance further the clinical outcomes of patients with EGFR mutant lung tumors.

Dataset Information

Mutational analysis of EGFR and related signaling pathway genes in lung adenocarcinomas identifies a novel somatic kinase domain mutation in FGFR4.

Publications

Mutational analysis of EGFR and related signaling pathway genes in lung adenocarcinomas identifies a novel somatic kinase domain mutation in FGFR4.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets