Format

Send to

Choose Destination
Oncotarget. 2016 Apr 26;7(17):23263-81. doi: 10.18632/oncotarget.8139.

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

Author information

1
Department of Medicine, BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA.
2
Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA.
3
Department of Molecular Cell Biology, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania.
4
Department of Electrical and Computer Engineering, University of Nebraska-Lincoln, Lincoln, NE, USA.
5
Division of Hematology and Oncology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA.

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.

KEYWORDS:

bioinformatics; biomarkers; meta-analysis; pancreatic cancer; transcriptome

PMID:
26993610
PMCID:
PMC5029625
DOI:
10.18632/oncotarget.8139
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Dr. M.K. Bhasin, Dr. R. Khosravi-Far and Dr. T.A. Libermann have ownership interest (including patents) in biomaRx Therapeutics, Inc. and are advisors to biomaRx Therapeutics, Inc.. Dr. M.K. Bhasin and Dr. T.A. Libermann have ownership interest in AnXome, Inc. and are advisors to AnXome, Inc.. No potential conflicts of interest were disclosed by the other authors.

Supplemental Content

Full text links

Icon for Impact Journals, LLC Icon for PubMed Central
Loading ...
Support Center