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



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.



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.
HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
Marie K
MK
Kirby
HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA; University of Alabama at Birmingham, Birmingham, AL, USA.
Ryne C
RC
Ramaker
HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
Jason
J
Gertz
HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
Nicholas S
NS
Davis
HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
Bobbi E
BE
Johnston
University of Alabama at Birmingham, Birmingham, AL, USA.
Patsy G
PG
Oliver
University of Alabama at Birmingham, Birmingham, AL, USA.
Katherine C
KC
Sexton
University of Minnesota, Minneapolis, MN, USA.
Edward W
EW
Greeno
University of Alabama at Birmingham, Birmingham, AL, USA.
John D
JD
Christein
University of Alabama at Birmingham, Birmingham, AL, USA.
Martin J
MJ
Heslin
University of Alabama at Birmingham, Birmingham, AL, USA.
James A
JA
Posey
University of Alabama at Birmingham, Birmingham, AL, USA.
William E
WE
Grizzle
University of Alabama at Birmingham, Birmingham, AL, USA.
Selwyn M
SM
Vickers
University of Alabama at Birmingham, Birmingham, AL, USA.
Donald J
DJ
Buchsbaum
HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
Sara J
SJ
Cooper
HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA. Electronic address: rmyers@hudsonalpha.org.
Richard M
RM
Myers
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000368:Aged; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012372:ROC Curve; D017423:Sequence Analysis, RNA / Q000379:methods*; D016019:Survival Analysis; D013997:Time Factors; D000093542:Gemcitabine
C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D012333:RNA, Messenger; D003841:Deoxycytidine; D000093542:Gemcitabine
ANGPTL4; Gemcitabine; Pancreatic adenocarcinoma; RNA-seq