Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Robust prognostic biomarkers for EAC identified by systems-level characterization of tumor transcriptome

ABSTRACT: Despite continual efforts to rationalize a prognostic stratification of patients with esophageal adenocarcinoma (EAC) before treatment, current staging system only shows limited success owing to the lack of molecular and genetic markers that reflect prognostic features of the tumor. To develop molecular predictors of prognosis, we used systems-level characterization of tumor transcriptome. Using DNA microarray, genome-wide gene expression profiling was performed on 75 biopsy samples from patients with untreated EAC. Various statistical and informatical methods were applied to gene expression data to identify potential biomarkers associated with prognosis. Potential marker genes were validated in an independent cohort using quantitiative RT-PCR to measure gene expression. Distinct subgroups of EAC were uncovered by systems-level characterization of tumor transcriptome. We also identified a six-gene expression signature that could be used to predict overall survival (OS) of EAC patients. In particular, expression of SPARC and SPP1 was a strong independent predictor of OS, and a combined gene expression signature with these two genes was associated with prognosis (P < 0.024), even when all relevant pathological variables were considered together in multivariate Cox hazard regression analysis. Our findings suggest that molecular features reflected in gene expression signatures may dictate the prognosis of EAC patients, and these gene expression signatures can be used to predict the likelihood of prognosis at the time of diagnosis and before treatment. 64 primary esophageal adenocarcinoma, 15 Barrett's esophagus and 28 surrounding normal fresh frozen tissues were used for microarray. All the tissues were obtained after curative resection after pathologic confirm at UT M.D. Anderson Cancer Center (MDACC). Microarray experiment and data analysis were done in the Dept. of systems biology at MDACC DNA microarray (Illumina human V2)

ORGANISM(S): Homo sapiens

SUBMITTER: Sangbae Kim

PROVIDER: E-GEOD-13898 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Prognostic biomarkers for esophageal adenocarcinoma identified by analysis of tumor transcriptome.

Kim Soo Mi SM Park Yun-Yong YY Park Eun Sung ES Cho Jae Yong JY Izzo Julie G JG Zhang Di D Kim Sang-Bae SB Lee Jeffrey H JH Bhutani Manoop S MS Swisher Stephen G SG Wu Xifeng X Coombes Kevin R KR Maru Dipen D Wang Kenneth K KK Buttar Navtej S NS Ajani Jaffer A JA Lee Ju-Seog JS

PloS one 20101130 11

<h4>Background</h4>Despite many attempts to establish pre-treatment prognostic markers to understand the clinical biology of esophageal adenocarcinoma (EAC), validated clinical biomarkers or parameters remain elusive. We generated and analyzed tumor transcriptome to develop a practical biomarker prognostic signature in EAC.<h4>Methodology/principal findings</h4>Untreated esophageal endoscopic biopsy specimens were obtained from 64 patients undergoing surgery and chemoradiation. Using DNA microar ...[more]

PMID: 21152079

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Project description:Esophageal cancers (ECs) are highly aggressive tumors with poor prognosis and few treatment options. This study investigated the possibility of treating esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) cells by inhibitors of broad and specific histone deacetylases (HDACi; SAHA, MS-275, FK228) and/or of DNMT (Azacytidine, AZA). Drug targets (HDAC1,2,3 and DNMT1) were present in non-neoplastic (HET-1A), ESCC (OE21) and EAC (OE33) cell lines. All cell lines responded to HDACi by reduced HDAC activity and increased histone acetylation as well as to AZA by up-regulation of p21. Expression of drug targets remained largely unaffected by HDACi and AZA treatment. Importantly, cell viability, apoptosis, cell cycle dynamics and DNA damage were only affected by HDACi and/or AZA in ESCC and EAC, but not the non-neoplastic cells. This was specifically seen for the combination of MS-275 and AZA, leading to enhanced cancer cell selectivity and drug efficiency. By transcriptome analyses of MS-275, AZA and MS-275/AZA treated cells, known (e.g. p21) as well as novel regulated genes significantly associated with the cellular effects post HDACi and/or AZA treatment in ESCC and EAC cells were identified. Finally, human EC tissue specimens frequently expressed the actionable drug targets HDAC1/2/3 and DNMT1. In summary, a combined HDACi (MS-275)/AZA treatment is cancer cell selective and efficient in vitro. Since the majority of ECs express the drug targets in situ, this paves the way for further investigations of HDACi/AZA treatment in esophageal cancer cells and their translation into a clinico-pathological setting. To elucidate the transcriptome response to HDAC inhibitors of normal esophageal cells and esophageal tumor cells, total RNA was isolated from non-neoplastic esophageal epithelial cells (Het1A cells) a well as from two esophageal tumor cell lines (OE21 and OE33), respectively. Cells were treated with either MS-275, Azacytidine (AZA) or in combination of both. DMSO treatment was used as control in each case. Total RNA was isolated from cells 24 h after treatment and experiments were performed in biological triplicates.

Dataset Information

Robust prognostic biomarkers for EAC identified by systems-level characterization of tumor transcriptome

Publications

Prognostic biomarkers for esophageal adenocarcinoma identified by analysis of tumor transcriptome.

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