title: Meta-analysis of transcriptome data identifies a novel 5-gene pancreatic adenocarcinoma classifier.
abstract: OBJECTIVE
  Pancreatic ductal adenocarcinoma (PDAC) is largely incurable due to late diagnosis. Superior early detection biomarkers are critical to improving PDAC survival and risk stratification.
  
  
  METHODS
  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.
authors.affiliation: Department of Medicine, BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Bhasin
authors.affiliation: Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Ndebele
authors.affiliation: Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA.|Department of Molecular Cell Biology, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania.
authors.forename: Octavian
authors.initials: O
authors.lastname: Bucur
authors.affiliation: Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Eric U
authors.initials: EU
authors.lastname: Yee
authors.affiliation: Department of Electrical and Computer Engineering, University of Nebraska-Lincoln, Lincoln, NE, USA.
authors.forename: Hasan H
authors.initials: HH
authors.lastname: Otu
authors.affiliation: Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Plati
authors.affiliation: Division of Hematology and Oncology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bullock
authors.affiliation: Department of Medicine, BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Gu
authors.affiliation: Department of Medicine, BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Castan
authors.affiliation: Department of Medicine, BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Najarian
authors.affiliation: Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Muraru
authors.affiliation: Division of Hematology and Oncology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Miksad
authors.affiliation: Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Roya
authors.initials: R
authors.lastname: Khosravi-Far
authors.affiliation: Department of Medicine, BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Towia A
authors.initials: TA
authors.lastname: Libermann
mesh_terms: D000230:Adenocarcinoma / Q000145:classification / Q000235:genetics* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics*; D002278:Carcinoma in Situ / Q000145:classification / Q000235:genetics / Q000473:pathology; D021441:Carcinoma, Pancreatic Ductal / Q000145:classification / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D018450:Disease Progression; D055088:Early Detection of Cancer; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012697:Serine Endopeptidases / Q000235:genetics*; D059467:Transcriptome
chemical_list: D014408:Biomarkers, Tumor; C489850:ECT2 protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D012697:Serine Endopeptidases; C528837:TMPRSS4 protein, human
keywords: bioinformatics; biomarkers; meta-analysis; pancreatic cancer; transcriptome