STAG2 is a clinically relevant tumor suppressor in pancreatic ductal adenocarcinoma

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.

Epigenetic inhibitors sensitize DLBCL cells to rituximab and doxorubicin

“…STAG2 is a central member of the cohesin complex and if inactivated by such mutations causes genome instability and aneuploidy ( 22 ). Knock-down of STAG2 is suggested to sensitize pancreatic ductal carcinoma to chemotherapy ( 23 ).…”

Integrated Patient-Derived Models Delineate Individualized Therapeutic Vulnerabilities of Pancreatic Cancer

“…This event can compromise mitotic fidelity and elicit sensitivity to DNA cross-linking agents (Evers et al, 2014; Solomon et al, 2011). Consistent with STAG2-deficiency, the PDX exhibited significant nuclear pleomorphism, mitotic aberrations, and high baseline DNA damage relative to other PDX models (Fig 1G).…”

Identification of MicroRNAs as Breast Cancer Prognosis Markers through the Cancer Genome Atlas

“…[74] STAG2 contributes to the cohesion complex and has been proposed as a prognostic biomarker for bladder and pancreatic cancer. [75–77] MSH2 appears to play a complex role in breast cancer biology in which expression of the gene can be associated with tumor suppression [78, 79] or oncogenesis [80–82] depending on the context. One possible explanation is that MSH2 may be downregulated as a breast cancer becomes invasive, but then MSH2 expression becomes associated with breast cancer progression as the continued proliferation of tumor cells requires increased DNA mismatch repair.…”