STAG2 is a clinically relevant tumor suppressor in pancreatic ductal adenocarcinoma.
BACKGROUND
Pancreatic ductal adenocarcinoma (PDA) is a highly lethal cancer characterized by complex aberrant genomes. A fundamental goal of current studies is to identify those somatic events arising in the variable landscape of PDA genomes that can be exploited for improved clinical outcomes.


METHODS
We used DNA content flow sorting to identify and purify tumor nuclei of PDA samples from 50 patients. The genome of each sorted sample was profiled by oligonucleotide comparative genomic hybridization and targeted resequencing of STAG2. Transposon insertions within STAG2 in a KRAS (G12D)-driven genetically engineered mouse model of PDA were screened by RT-PCR. We then used a tissue microarray to survey STAG2 protein expression levels in 344 human PDA tumor samples and adjacent tissues. Univariate Kaplan Meier analysis and multivariate Cox Regression analysis were used to assess the association of STAG2 expression relative to overall survival and response to adjuvant therapy. Finally, RNAi-based assays with PDA cell lines were used to assess the potential therapeutic consequence of STAG2 expression in response to 18 therapeutic agents.


RESULTS
STAG2 is targeted by somatic aberrations in a subset (4%) of human PDAs. Transposon-mediated disruption of STAG2 in a KRAS (G12D) genetically engineered mouse model promotes the development of PDA and its progression to metastatic disease. There was a statistically significant loss of STAG2 protein expression in human tumor tissue (Wilcoxon-Rank test) with complete absence of STAG2 staining observed in 15 (4.3%) patients. In univariate Kaplan Meier analysis nearly complete STAG2 positive staining (>95% of nuclei positive) was associated with a median survival benefit of 6.41 months (P = 0.031). The survival benefit of adjuvant chemotherapy was only seen in patients with a STAG2 staining of less than 95% (median survival benefit 7.65 months; P = 0.028). Multivariate Cox Regression analysis showed that STAG2 is an independent prognostic factor for survival in pancreatic cancer patients. Finally, we show that RNAi-mediated knockdown of STAG2 selectively sensitizes human PDA cell lines to platinum-based therapy.


CONCLUSIONS
Based on these iterative findings we propose that STAG2 is a clinically significant tumor suppressor in PDA.
Clinical Translational Research Division, Translational Genomics Research Institute, Scottsdale, AZ 85259, USA.
Lisa
L
Evers
CRUK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
Pedro A
PA
Perez-Mancera
Clinical Translational Research Division, Translational Genomics Research Institute, Scottsdale, AZ 85259, USA.
Elizabeth
E
Lenkiewicz
Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA.
Nanyun
N
Tang
Institute of Pathology, University Hospital Dresden, Fetscherstr, 74, 01307 Dresden, Germany.
Daniela
D
Aust
Institute of Pathology, Ludwig-Maximilians-University (LMU), Thalkirchnerstr. 36, 80337 Munich, Germany.
Thomas
T
Knösel
Institute of Pathology, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany.
Petra
P
Rümmele
Clinical Translational Research Division, Translational Genomics Research Institute, Scottsdale, AZ 85259, USA.
Tara
T
Holley
Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA.
Michelle
M
Kassner
Clinical Translational Research Division, Translational Genomics Research Institute, Scottsdale, AZ 85259, USA.
Meraj
M
Aziz
Clinical Translational Research Division, Translational Genomics Research Institute, Scottsdale, AZ 85259, USA ; Virginia G. Piper Cancer Center, Scottsdale Healthcare, Scottsdale, AZ 85258, USA.
Ramesh K
RK
Ramanathan
Clinical Translational Research Division, Translational Genomics Research Institute, Scottsdale, AZ 85259, USA ; Virginia G. Piper Cancer Center, Scottsdale Healthcare, Scottsdale, AZ 85258, USA.
Daniel D
DD
Von Hoff
Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA.
Holly
H
Yin
Department of Surgery, University Hospital Dresden, Fetscherstr, 74, 01307 Dresden, Germany.
Christian
C
Pilarsky
Clinical Translational Research Division, Translational Genomics Research Institute, Scottsdale, AZ 85259, USA.
Michael T
MT
Barrett