Expression Profile-Defined Classification of Lung Adenocarcinoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE11969 | GEO | 2009/04/01
SECONDARY ACCESSION(S): PRJNA105841
REPOSITORIES: GEO
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Project description:Expression profiles of 18,175 unique genes and three major genetic changes, p53, EGFR and K-ras, were investigated in 149 patients with non-small cell lung cancer (NSCLC), including 90 patients with adenocarcinomas (AD) to determine their relationships with various clinicopathologic features and Gene Ontology (GO) terms. Keywords: Disease state analysis Expression profiles in 149 patients with NSCLC, 9 patients with SCLC and 5 for normal lung tissue.
2009-04-01 | E-GEOD-11969 | biostudies-arrayexpress
Project description:PURPOSE: Although epidermal growth factor receptor (EGFR) mutated adenocarcinomas initially have very high response rates to EGFR tyrosine kinase inhibitors (TKIs), most atients eventually develop resistance. Patient derived xenografts (PDXs) are considered preferred preclinical models to study the biology of patient tumors. EGFR-mutant PDX models may be valuable tools to study the biology of these tumors and to elucidate mechanisms of resistance to EGFR-targeted therapies. METHODS: Surgically resected early stage non-small cell lung carcinoma (NSCLC) tumors were implanted into non-obese diabetic severe combined immune deficient (NODSCID) mice. EGFR TKI treatment was initiated at tumor volumes of 150 mm3. Gene expression analysis was performed using microarray platform. RESULTS: Of 33 lung adenocarcinomas with EGFR activating mutations, only 6 engrafted 18%) and could be propagated beyond passage one. Engraftment was associated with upregulation of genes involved in mitotic checkpoint and cell proliferation. A differentially expressed gene set between engrafting and non-engrafting patients could identify EGFRmutant patients with significantly different prognoses in The Cancer Genome Atlas (TCGA) Lung Adenocarcinoma datasets. The PDXs included models with variable sensitivity to first- and second-generation EGFR TKIs and the monoclonal antibody cetuximab. All EGFR-mutant NSCLC PDXs studied closely recapitulated their corresponding patient tumor phenotype and clinical course, including response pattern to EGFR TKIs. CONCLUSIONS: PDX models closely recapitulate primary tumor biology and clinical outcome. They may serve as important laboratory models to investigate mechanisms of resistance to targeted therapies, and for preclinical testing of novel treatment strategies.
2017-03-28 | GSE63685 | GEO
Project description:Whole exome sequencing was performed on set of 48 DNA samples obtained from 16 EGFR mutated NSCLC patients whose tumors progressed following EGFR-TKI treatment. The DNA samples included baseline biopsy, rebiopsy and blood from the same patient. By comparing the variants in rebiopsy tumors and baseline tumors we aim to understand the genomic alterations responsible for the development of EGFR-TKI resistance in NSCLC patients.
2022-02-11 | E-MTAB-11404 | biostudies-arrayexpress
Project description:Purpose: To determine the 8-week disease control rate (DCR) of sorafenib monotherapy in patients with advanced non-small-cell lung cancer (NSCLC) in the BATTLE trial. Methods: Patients with pre-treated NSCLC, ECOG performance status (PS) 0-2, consented to biopsies to test for biomarker assessment. Sorafenib was given at 400 mg orally twice daily until tumor progression or an unacceptable toxicity. Tumor evaluations were performed at baseline and every 8 weeks. Correlations of outcomes by biomarker groups were analyzed. Results: 105 patients were eligible and 98 patients were evaluable. Median age was 62 (range 34-81) years, 51% of patients were male, 75% were former/current smokers, and 89% had an ECOG PS of 0-1. Median prior chemotherapies for stage IV NSCLC were two. Median follow-up was 9.4 (range: 1.3-32.2) months. Eight-week DCRs by histology were 59.1%, 57.1%, and 55.6% for adenocarcinomas, squamous cell carcinomas and other histologies respectively. Patients with tumors harboring EGFR mutations had significantly lower 8-week DCR compared to patients with wild-type tumors (23.1% vs. 64.2%, P=0.0119), and patients with tumors harboring K-RAS mutations had the highest 8-week DCR (67%). Most commonly reported treatment-related adverse events include hand-foot syndrome (59.6%), fatigue (42.3%), rash (40.4%), diarrhea (38.5%), and weight loss (38.5%). Conclusion: 8-week DCR was better in patients treated with sorafenib who had EGFR wild-type tumors (including those with K-RAS mutations) when compared to those who had EGFR mutations. Additional analyses are warranted to further explore the biology of these tumors and related patient outcomes with sorafenib treatment. ClinicalTrials.gov number, NCT00411671.
2012-06-18 | GSE32036 | GEO
Project description:Purpose: To determine the 8-week disease control rate (DCR) of sorafenib monotherapy in patients with advanced non-small-cell lung cancer (NSCLC) in the BATTLE trial. Methods: Patients with pre-treated NSCLC consented to baseline biopsies for pre-specified biomarkers assessment and biomarker discovery. Sorafenib was given at 400 mg orally twice daily until tumor progression or unacceptable toxicity. Outcomes by pre-specified biomarkers were analyzed and a Sorafenib sensitivity signature developed using high-throughput gene expression profiles of NSCLC cell lines and baseline biopsies. Results: 105 patients were eligible and 98 patients were evaluable. Median age was 62 (range 34-81) years, 51% of patients were male, 75% were former/current smokers, and 89% had an ECOG performance status of 0-1. Median prior chemotherapies for stage IV NSCLC were two. Median follow-up was 9.4 (range: 1.3-32.2) months. Overall, 8-week DCR was 58.2%. Patients with EGFR mutations had significantly lower 8-week DCR compared to patients with wild-type tumors (23.1% vs. 64.2%, P=0.0119), and patients with K-RAS mutations had the highest 8-week DCR (67%). Most commonly reported treatment-related adverse events include hand-foot syndrome (59.6%), fatigue (42.3%), rash (40.4%), diarrhea (38.5%), and weight loss (38.5%). Sorafenib sensitivity signature developed in cell lines was associated with an improved outcome. Conclusion: Patients with wild-type EGFR, including those with K-RAS mutation, may benefit from sorafenib as opposed to patients with EGFR mutation. We identify a gene expression signature associated with an improved outcome in patients with wild-type EGFR treated with sorafenib. BATTLE-2 trial is ongoing to validate those results. ClinicalTrials.gov number, NCT00411671. Gene expression profiles were measured in 37 core biopsies from patients with refractory non-small cell lung cancer treated with sorafenib in the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial. We report a Sorafenib sensitivity gene expression signature trained in vitro (separate GEO submission), and tested in baseline biopsies collected in the BATTLE trial.
2014-06-01 | E-GEOD-31428 | biostudies-arrayexpress
Project description:EGFR-mutated non-small cell lung cancers bear hallmarks including sensitivity to EGFR inhibitors, and low proliferation, and increased MET. However, the biology of EGFR dependence is still poorly understood. Using a training cohort of chemo-naive lung adenocarcinomas, we have developed a 72-gene signature that predicts (i) EGFR mutation status in four independent datasets; (ii) sensitivity to erlotinib in vitro; and (iii) improved survival, even in the wild-type EGFR subgroup. The signature includes differences associated with enhanced receptor tyrosine kinase (RTK) signaling, such as increased expression of endocytosis-related genes, decreased phosphatase levels, decreased expression of proliferation-related genes, increased folate receptor-1 (FOLR1) (a determinant of pemetrexed response), and higher levels of MACC1 (which we identify as a regulator of MET in EGFR-mutant NSCLC). Those observations provide evidence that the EGFR-mutant phenotype is associated with alterations in the cellular machinery that links the EGFR and MET pathways and create a permissive environment for RTK signaling. We have developed a gene expression signature that predicts (i) EGFR mutation in chemo-naive and, to a lesser extent, in chemo-refractory NSCLC patients; (ii) EGFR TKI response in vitro; and (iii) survival in wild-type EGFR patients. The signature also identifies novel features of EGFR mutant NSCLC including increased levels of endocytosis-related genes and MACC1, which appears be an EGFR mutant associated regulator of MET. Gene expression profiles were measured in 124 core biopsies from patients with refractory non-small cell lung cancer in the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial. We used the BATTLE dataset to test an EGFR-mutation gene expression signature trained in chemo-naive lung adenocarcinoma. The signature was computed as an index, called EGFR index.
2014-06-01 | E-GEOD-31852 | biostudies-arrayexpress
Project description:The study was designed to identify the molecular changes that occur in EGFR mutant NSCLCs that become resistant to TKI by transforming to SCLC. Tyrosine kinase inhibitors (TKIs) are effective treatments for non-small cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, they do not lead to cures, and, on average, relapse occurs after one year of continuous treatment. In a subset of patients, a fundamental histological transformation from NSCLC to small cell lung cancer (SCLC) is observed in the resistant cancers, but the molecular changes associated with this transformation remain unknown. Analysis of a cohort of tumor samples and cell lines derived from resistant EGFR mutant patients with SCLC transformation revealed that RB is lost in 100% of these cases, but rarely in those that remain NSCLC. Global changes in gene expression, including increased neuroendocrine marker expression and absence of EGFR expression, are observed in cancers that transformed to SCLC. Consistent with their genetic and epigenetic similarities to classical SCLC, cell lines derived from resistant EGFR mutant SCLC biopsies are substantially more sensitive to ABT-263 treatment compared to those derived from resistant EGFR mutant NSCLCs. Together, these findings suggest that despite developing initially as EGFR mutant adenocarcinomas, this subset of resistant cancers ultimately take on many of the molecular and phenotypic characteristics of classical SCLC. Overall, we completed array CGH analysis on 4 tumor specimens from EGFR mutant, TKI-resistant patients. Three of these samples had transformed to SCLC and one remained NSCLC.
2015-01-30 | E-GEOD-64765 | biostudies-arrayexpress
Project description:EGFR-mutated non-small cell lung cancers bear hallmarks including sensitivity to EGFR inhibitors, and low proliferation, and increased MET. However, the biology of EGFR dependence is still poorly understood. Using a training cohort of chemo-naive lung adenocarcinomas, we have developed a 72-gene signature that predicts (i) EGFR mutation status in four independent datasets; (ii) sensitivity to erlotinib in vitro; and (iii) improved survival, even in the wild-type EGFR subgroup. The signature includes differences associated with enhanced receptor tyrosine kinase (RTK) signaling, such as increased expression of endocytosis-related genes, decreased phosphatase levels, decreased expression of proliferation-related genes, increased folate receptor-1 (FOLR1) (a determinant of pemetrexed response), and higher levels of MACC1 (which we identify as a regulator of MET in EGFR-mutant NSCLC). Those observations provide evidence that the EGFR-mutant phenotype is associated with alterations in the cellular machinery that links the EGFR and MET pathways and create a permissive environment for RTK signaling. We have developed a gene expression signature that predicts (i) EGFR mutation in chemo-naive and, to a lesser extent, in chemo-refractory NSCLC patients; (ii) EGFR TKI response in vitro; and (iii) survival in wild-type EGFR patients. The signature also identifies novel features of EGFR mutant NSCLC including increased levels of endocytosis-related genes and MACC1, which appears be an EGFR mutant associated regulator of MET.
2014-06-01 | GSE31852 | GEO
Project description:Purpose: To determine the 8-week disease control rate (DCR) of sorafenib monotherapy in patients with advanced non-small-cell lung cancer (NSCLC) in the BATTLE trial. Methods: Patients with pre-treated NSCLC consented to baseline biopsies for pre-specified biomarkers assessment and biomarker discovery. Sorafenib was given at 400 mg orally twice daily until tumor progression or unacceptable toxicity. Outcomes by pre-specified biomarkers were analyzed and a Sorafenib sensitivity signature developed using high-throughput gene expression profiles of NSCLC cell lines and baseline biopsies. Results: 105 patients were eligible and 98 patients were evaluable. Median age was 62 (range 34-81) years, 51% of patients were male, 75% were former/current smokers, and 89% had an ECOG performance status of 0-1. Median prior chemotherapies for stage IV NSCLC were two. Median follow-up was 9.4 (range: 1.3-32.2) months. Overall, 8-week DCR was 58.2%. Patients with EGFR mutations had significantly lower 8-week DCR compared to patients with wild-type tumors (23.1% vs. 64.2%, P=0.0119), and patients with K-RAS mutations had the highest 8-week DCR (67%). Most commonly reported treatment-related adverse events include hand-foot syndrome (59.6%), fatigue (42.3%), rash (40.4%), diarrhea (38.5%), and weight loss (38.5%). Sorafenib sensitivity signature developed in cell lines was associated with an improved outcome. Conclusion: Patients with wild-type EGFR, including those with K-RAS mutation, may benefit from sorafenib as opposed to patients with EGFR mutation. We identify a gene expression signature associated with an improved outcome in patients with wild-type EGFR treated with sorafenib. BATTLE-2 trial is ongoing to validate those results. ClinicalTrials.gov number, NCT00411671.
2014-06-01 | GSE31428 | GEO
Project description:Affymetrix Human Genome U133A platform was used to obtain gene expression profiles of 28 pathologically and clinically well characterized adenocarcinomas of the lung. In addition, EGFR status was determined by fluorescent in situ hybridization and immunohistochemistry. The classification of the cases using a clustering algorithm applied to the expression data correlated significantly with the histopathological tumor grades. In contrast, no correlation of gene expression data and EGFR status could be detected. In this study we evaluated the gene expression of 28 clinico-pathological well characterized lung adenocarcinomas.
2009-08-04 | E-GEOD-17475 | biostudies-arrayexpress