title: RNA Sequencing Identifies Transcriptionally Viable Gene Fusions in Esophageal Adenocarcinomas.
abstract: Esophageal adenocarcinoma is a deadly cancer with increasing incidence in the United States, but mechanisms underlying pathogenesis are still mostly elusive. In addressing this question, we assessed gene fusion landscapes by comprehensive RNA sequencing (RNAseq) of 55 pretreatment esophageal adenocarcinoma and 49 nonmalignant biopsy tissues from patients undergoing endoscopy for Barrett's esophagus. In this cohort, we identified 21 novel candidate esophageal adenocarcinoma-associated fusions occurring in 3.33% to 11.67% of esophageal adenocarcinomas. Two candidate fusions were selected for validation by PCR and Sanger sequencing in an independent set of pretreatment esophageal adenocarcinoma (N = 115) and nonmalignant (N = 183) biopsy tissues. In particular, we observed RPS6KB1-VMP1 gene fusion as a recurrent event occurring in approximately 10% of esophageal adenocarcinoma cases. Notably, esophageal adenocarcinoma cases harboring RPS6KB1-VMP1 fusions exhibited significantly poorer overall survival as compared with fusion-negative cases. Mechanistic investigations established that the RPS6KB1-VMP1 transcript coded for a fusion protein, which significantly enhanced the growth rate of nondysplastic Barrett's esophagus cells. Compared with the wild-type VMP1 protein, which mediates normal cellular autophagy, RPS6KB1-VMP1 fusion exhibited aberrant subcellular localization and was relatively ineffective in triggering autophagy. Overall, our findings identified RPS6KB1-VMP1 as a genetic fusion that promotes esophageal adenocarcinoma by modulating autophagy-related processes, offering new insights into the molecular pathogenesis of esophageal adenocarcinomas. Cancer Res; 76(19); 5628-33. ©2016 AACR.
authors: Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
authors: Andrew E
authors: AE
authors: Blum
authors: Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
authors: Srividya
authors: S
authors: Venkitachalam
authors: Center for Quantitative Sciences, Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
authors: Yan
authors: Y
authors: Guo
authors: Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
authors: Ann Marie
authors: AM
authors: Kieber-Emmons
authors: Division of Hematology and Oncology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
authors: Lakshmeswari
authors: L
authors: Ravi
authors: Division of Gastroenterology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
authors: Apoorva K
authors: AK
authors: Chandar
authors: Barrett's Esophagus Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
authors: Prasad G
authors: PG
authors: Iyer
authors: Division of Gastroenterology and Hepatology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors: Marcia I
authors: MI
authors: Canto
authors: Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors: Jean S
authors: JS
authors: Wang
authors: Division of Gastroenterology and Hepatology, Center for Esophageal Diseases and Swallowing, University of North Carolina, Chapel Hill, North Carolina.
authors: Nicholas J
authors: NJ
authors: Shaheen
authors: Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
authors: Jill S
authors: JS
authors: Barnholtz-Sloan
authors: Department of Medicine, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
authors: Sanford D
authors: SD
authors: Markowitz
authors: Department of Pathology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
authors: Joseph E
authors: JE
authors: Willis
authors: Center for Quantitative Sciences, Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
authors: Yu
authors: Y
authors: Shyr
authors: Division of Gastroenterology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
authors: Amitabh
authors: A
authors: Chak
authors: Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
authors: Vinay
authors: V
authors: Varadan
authors: Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio. kkg5@case.edu.
authors: Kishore
authors: K
authors: Guda
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D001343:Autophagy; D045744:Cell Line, Tumor; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D050939:Gene Fusion; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics*; D017423:Sequence Analysis, RNA
chemical_list: D008565:Membrane Proteins; C526584:VMP1 protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1