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Abstract
BackgroundPancreatic 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.MethodsWe 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 KRASG12D-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.ResultsSTAG2 is targeted by somatic aberrations in a subset (4%) of human PDAs. Transposon-mediated disruption of STAG2 in a KRASG12D 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.ConclusionsBased on these iterative findings we propose that STAG2 is a clinically significant tumor suppressor in PDA.
Highlights
Pancreatic ductal adenocarcinoma (PDA) is a highly lethal cancer characterized by complex aberrant genomes
The same homozygous deletion was detected in the 4.5 N aneuploid populations found in the two distinct distant metastatic sites surveyed within the same patient
The presence of the same somatic homozygous deletion within a 4.5 N PDA population in each anatomical site suggests that cells that lost STAG2 arose early in the history of this tumor and contributed to its progression to metastatic disease
Summary
Pancreatic ductal adenocarcinoma (PDA) is a highly lethal cancer characterized by complex aberrant genomes. A genetic hallmark of pancreatic ductal adenocarcinoma (PDA) is the presence of somatic KRAS mutations in over 90 to 95% of tumors, the most prevalent being KRASG12D [1,2]. A fundamental question remains the identification of somatic aberrations arising in the complex genomic landscape of PDA that drive the progression of KRAS patients in vivo [5,6,7]. Somatic aberrations and loss of STAG2 expression have been reported in a subset of tumors and cell lines, including melanomas, sarcomas, and glioblastomas [3]. The development of a KRASG12D-driven genetically engineered mouse (GEM) model of PDA has provided a powerful resource for the study of the events that accelerate tumorigenesis and drive tumor progression in the pancreas [9]. The clinical significance of STAG2 expression and its role as a tumor suppressor gene in human PDA remains to be elucidated
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