Meta-analysis of transcriptome data identifies a novel 5-gene pancreatic adenocarcinoma classifier

Manoj K. Bhasin, Kenneth Ndebele, Octavian Bucur, Eric U. Yee, Hasan H. Otu, Jessica Plati, Andrea Bullock, Xuesong Gu, Eduardo Castan, Peng Zhang, Robert Najarian, Maria S. Muraru, Rebecca Miksad, Roya Khosravi-Far, Towia A. Libermann

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is largely incurable due to late diagnosis. Superior early detection biomarkers are critical to improving PDAC survival and risk stratification. Experimental Design: Optimized meta-analysis of PDAC transcriptome datasets identified and validated key PDAC biomarkers. PDAC-specific expression of a 5-gene biomarker panel was measured by qRT-PCR in microdissected patient-derived FFPE tissues. Cell-based assays assessed impact of two of these biomarkers, TMPRSS4 and ECT2, on PDAC cells. Results: A 5-gene PDAC classifier (TMPRSS4, AHNAK2, POSTN, ECT2, SERPINB5) achieved on average 95% sensitivity and 89% specificity in discriminating PDAC from non-tumor samples in four training sets and similar performance (sensitivity = 94%, specificity = 89.6%) in five independent validation datasets. This classifier accurately discriminated PDAC from chronic pancreatitis (AUC = 0.83), other cancers (AUC = 0.89), and non-tumor from PDAC precursors (AUC = 0.92) in three independent datasets. Importantly, the classifier distinguished PanIN from healthy pancreas in the PDX1-Cre;LSL-KrasG12D PDAC mouse model. Discriminatory expression of the PDAC classifier genes was confirmed in microdissected FFPE samples of PDAC and matched surrounding non-tumor pancreas or pancreatitis. Notably, knock-down of TMPRSS4 and ECT2 reduced PDAC soft agar growth and cell viability and TMPRSS4 knockdown also blocked PDAC migration and invasion. Conclusions: This study identified and validated a highly accurate 5-gene PDAC classifier for discriminating PDAC and early precursor lesions from non-malignant tissue that may facilitate early diagnosis and risk stratification upon validation in prospective clinical trials. Cell-based experiments of two overexpressed proteins encoded by the panel, TMPRSS4 and ECT2, suggest a causal link to PDAC development and progression, confirming them as potential therapeutic targets.

Original languageEnglish (US)
Pages (from-to)23263-23281
Number of pages19
JournalOncotarget
Volume7
Issue number17
DOIs
StatePublished - Apr 26 2016

Fingerprint

Transcriptome
Meta-Analysis
Adenocarcinoma
Genes
Biomarkers
Area Under Curve
Pancreas
Sensitivity and Specificity
Delayed Diagnosis
Chronic Pancreatitis
Pancreatitis
Agar

Keywords

  • Bioinformatics
  • Biomarkers
  • Meta-analysis
  • Pancreatic cancer
  • Transcriptome

ASJC Scopus subject areas

  • Oncology

Cite this

Bhasin, M. K., Ndebele, K., Bucur, O., Yee, E. U., Otu, H. H., Plati, J., ... Libermann, T. A. (2016). Meta-analysis of transcriptome data identifies a novel 5-gene pancreatic adenocarcinoma classifier. Oncotarget, 7(17), 23263-23281. https://doi.org/10.18632/oncotarget.8139

Meta-analysis of transcriptome data identifies a novel 5-gene pancreatic adenocarcinoma classifier. / Bhasin, Manoj K.; Ndebele, Kenneth; Bucur, Octavian; Yee, Eric U.; Otu, Hasan H.; Plati, Jessica; Bullock, Andrea; Gu, Xuesong; Castan, Eduardo; Zhang, Peng; Najarian, Robert; Muraru, Maria S.; Miksad, Rebecca; Khosravi-Far, Roya; Libermann, Towia A.

In: Oncotarget, Vol. 7, No. 17, 26.04.2016, p. 23263-23281.

Research output: Contribution to journalArticle

Bhasin, MK, Ndebele, K, Bucur, O, Yee, EU, Otu, HH, Plati, J, Bullock, A, Gu, X, Castan, E, Zhang, P, Najarian, R, Muraru, MS, Miksad, R, Khosravi-Far, R & Libermann, TA 2016, 'Meta-analysis of transcriptome data identifies a novel 5-gene pancreatic adenocarcinoma classifier', Oncotarget, vol. 7, no. 17, pp. 23263-23281. https://doi.org/10.18632/oncotarget.8139
Bhasin, Manoj K. ; Ndebele, Kenneth ; Bucur, Octavian ; Yee, Eric U. ; Otu, Hasan H. ; Plati, Jessica ; Bullock, Andrea ; Gu, Xuesong ; Castan, Eduardo ; Zhang, Peng ; Najarian, Robert ; Muraru, Maria S. ; Miksad, Rebecca ; Khosravi-Far, Roya ; Libermann, Towia A. / Meta-analysis of transcriptome data identifies a novel 5-gene pancreatic adenocarcinoma classifier. In: Oncotarget. 2016 ; Vol. 7, No. 17. pp. 23263-23281.
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abstract = "Purpose: Pancreatic ductal adenocarcinoma (PDAC) is largely incurable due to late diagnosis. Superior early detection biomarkers are critical to improving PDAC survival and risk stratification. Experimental Design: Optimized meta-analysis of PDAC transcriptome datasets identified and validated key PDAC biomarkers. PDAC-specific expression of a 5-gene biomarker panel was measured by qRT-PCR in microdissected patient-derived FFPE tissues. Cell-based assays assessed impact of two of these biomarkers, TMPRSS4 and ECT2, on PDAC cells. Results: A 5-gene PDAC classifier (TMPRSS4, AHNAK2, POSTN, ECT2, SERPINB5) achieved on average 95{\%} sensitivity and 89{\%} specificity in discriminating PDAC from non-tumor samples in four training sets and similar performance (sensitivity = 94{\%}, specificity = 89.6{\%}) in five independent validation datasets. This classifier accurately discriminated PDAC from chronic pancreatitis (AUC = 0.83), other cancers (AUC = 0.89), and non-tumor from PDAC precursors (AUC = 0.92) in three independent datasets. Importantly, the classifier distinguished PanIN from healthy pancreas in the PDX1-Cre;LSL-KrasG12D PDAC mouse model. Discriminatory expression of the PDAC classifier genes was confirmed in microdissected FFPE samples of PDAC and matched surrounding non-tumor pancreas or pancreatitis. Notably, knock-down of TMPRSS4 and ECT2 reduced PDAC soft agar growth and cell viability and TMPRSS4 knockdown also blocked PDAC migration and invasion. Conclusions: This study identified and validated a highly accurate 5-gene PDAC classifier for discriminating PDAC and early precursor lesions from non-malignant tissue that may facilitate early diagnosis and risk stratification upon validation in prospective clinical trials. Cell-based experiments of two overexpressed proteins encoded by the panel, TMPRSS4 and ECT2, suggest a causal link to PDAC development and progression, confirming them as potential therapeutic targets.",
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AU - Ndebele, Kenneth

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AU - Otu, Hasan H.

AU - Plati, Jessica

AU - Bullock, Andrea

AU - Gu, Xuesong

AU - Castan, Eduardo

AU - Zhang, Peng

AU - Najarian, Robert

AU - Muraru, Maria S.

AU - Miksad, Rebecca

AU - Khosravi-Far, Roya

AU - Libermann, Towia A.

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N2 - Purpose: Pancreatic ductal adenocarcinoma (PDAC) is largely incurable due to late diagnosis. Superior early detection biomarkers are critical to improving PDAC survival and risk stratification. Experimental Design: Optimized meta-analysis of PDAC transcriptome datasets identified and validated key PDAC biomarkers. PDAC-specific expression of a 5-gene biomarker panel was measured by qRT-PCR in microdissected patient-derived FFPE tissues. Cell-based assays assessed impact of two of these biomarkers, TMPRSS4 and ECT2, on PDAC cells. Results: A 5-gene PDAC classifier (TMPRSS4, AHNAK2, POSTN, ECT2, SERPINB5) achieved on average 95% sensitivity and 89% specificity in discriminating PDAC from non-tumor samples in four training sets and similar performance (sensitivity = 94%, specificity = 89.6%) in five independent validation datasets. This classifier accurately discriminated PDAC from chronic pancreatitis (AUC = 0.83), other cancers (AUC = 0.89), and non-tumor from PDAC precursors (AUC = 0.92) in three independent datasets. Importantly, the classifier distinguished PanIN from healthy pancreas in the PDX1-Cre;LSL-KrasG12D PDAC mouse model. Discriminatory expression of the PDAC classifier genes was confirmed in microdissected FFPE samples of PDAC and matched surrounding non-tumor pancreas or pancreatitis. Notably, knock-down of TMPRSS4 and ECT2 reduced PDAC soft agar growth and cell viability and TMPRSS4 knockdown also blocked PDAC migration and invasion. Conclusions: This study identified and validated a highly accurate 5-gene PDAC classifier for discriminating PDAC and early precursor lesions from non-malignant tissue that may facilitate early diagnosis and risk stratification upon validation in prospective clinical trials. Cell-based experiments of two overexpressed proteins encoded by the panel, TMPRSS4 and ECT2, suggest a causal link to PDAC development and progression, confirming them as potential therapeutic targets.

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KW - Pancreatic cancer

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