RNA sequencing of pancreatic adenocarcinoma tumors yields novel expression patterns associated with long-term survival and reveals a role for ANGPTL4

Marie K. Kirby, Ryne C. Ramaker, Jason Gertz, Nicholas S. Davis, Bobbi E. Johnston, Patsy G. Oliver, Katherine C. Sexton, Edward W. Greeno, John D. Christein, Martin J. Heslin, James A. Posey, William E. Grizzle, Selwyn M. Vickers, Donald J. Buchsbaum, Sara J. Cooper, Richard M. Myers

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Background Pancreatic adenocarcinoma patients have low survival rates due to late-stage diagnosis and high rates of cancer recurrence even after surgical resection. It is important to understand the molecular characteristics associated with survival differences in pancreatic adenocarcinoma tumors that may inform patient care. Results RNA sequencing was performed for 51 patient tumor tissues extracted from patients undergoing surgical resection, and expression was associated with overall survival time from diagnosis. Our analysis uncovered 323 transcripts whose expression correlates with survival time in our pancreatic patient cohort. This genomic signature was validated in an independent RNA-seq dataset of 68 additional patients from the International Cancer Genome Consortium. We demonstrate that this transcriptional profile is largely independent of markers of cellular division and present a 19-transcript predictive model built from a subset of the 323 transcripts that can distinguish patients with differing survival times across both the training and validation patient cohorts. We present evidence that a subset of the survival-associated transcripts is associated with resistance to gemcitabine treatment in vitro, and reveal that reduced expression of one of the survival-associated transcripts, Angiopoietin-like 4, impairs growth of a gemcitabine-resistant pancreatic cancer cell line. Conclusions Gene expression patterns in pancreatic adenocarcinoma tumors can distinguish patients with differing survival outcomes after undergoing surgical resection, and the survival difference could be associated with the intrinsic gemcitabine sensitivity of primary patient tumors. Thus, these transcriptional differences may impact patient care by distinguishing patients who would benefit from a non-gemcitabine based therapy.

Original languageEnglish (US)
Pages (from-to)1169-1182
Number of pages14
JournalMolecular Oncology
Volume10
Issue number8
DOIs
StatePublished - Oct 1 2016

Bibliographical note

Funding Information:
This work was funded by the UAB/UMN SPORE in Pancreatic Cancer ( P50CA101955 ), the NIH-National Institute of General Medical Sciences Medical Scientist Training Program ( 5T32GM008361-21 ), and by The State of Alabama and the HudsonAlpha Institute.

Publisher Copyright:
© 2016 Federation of European Biochemical Societies

Keywords

  • ANGPTL4
  • Gemcitabine
  • Pancreatic adenocarcinoma
  • RNA-seq

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