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

Authors

• Manoj K. Bhasin, Harvard Medical School
• Kenneth Ndebele, Harvard Medical School
• Octavian Bucur, Harvard Medical School
• Eric U. Yee, Harvard Medical School
• Hasan H. Otu, University of Nebraska-LincolnFollow
• Jessica Plati, Harvard Medical School
• Andrea Bullock, Harvard Medical School
• Xuesong Gu, Harvard Medical School
• Eduardo Castan, University of Nebraska-Lincoln
• Peng Zhang, Harvard Medical School
• Robert Najarian, Harvard Medical School
• Maria S. Muraru, Harvard Medical School
• Rebecca Miksad, Harvard Medical School
• Roya Khosravi-Far, Harvard Medical SchoolFollow
• Towia A. Libermann, Harvard Medical SchoolFollow

Document Type

Article

Date of this Version

2016

Citation

Oncotarget, Vol. 7, No. 17

Comments

This document is published under a Creative Commons/Open Access license.

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-Kras^G12D 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.