RNA sequencing identifies transcriptionally viable gene fusions in esophageal adenocarcinomas

Andrew E. Blum, Srividya Venkitachalam, Yan Guo, Ann Marie Kieber-Emmons, Lakshmeswari Ravi, Apoorva K. Chandar, Prasad G. Iyer, Marcia I. Canto, Jean S. Wang, Nicholas J. Shaheen, Jill S. Barnholtz-Sloan, Sanford D. Markowitz, Joseph E. Willis, Yu Shyr, Amitabh Chak, Vinay Varadan, Kishore Guda

Research output: Contribution to journalArticle

14 Scopus citations

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 adenocarcinomaand 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.

Original languageEnglish (US)
Pages (from-to)5628-5633
Number of pages6
JournalCancer research
Volume76
Issue number19
DOIs
StatePublished - Oct 1 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Blum, A. E., Venkitachalam, S., Guo, Y., Kieber-Emmons, A. M., Ravi, L., Chandar, A. K., Iyer, P. G., Canto, M. I., Wang, J. S., Shaheen, N. J., Barnholtz-Sloan, J. S., Markowitz, S. D., Willis, J. E., Shyr, Y., Chak, A., Varadan, V., & Guda, K. (2016). RNA sequencing identifies transcriptionally viable gene fusions in esophageal adenocarcinomas. Cancer research, 76(19), 5628-5633. https://doi.org/10.1158/0008-5472.CAN-16-0979