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STAG2 is a clinically relevant tumor suppressor in pancreatic ductal adenocarcinoma
Lisa Evers1, Pedro A Perez-Mancera2, Elizabeth Lenkiewicz1
1Clinical Translational Research Division, Translational Genomics Research Institute, Scottsdale, AZ 85259, USA.
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.
Insights
STAG2 loss is linked to pancreatic ductal adenocarcinoma (PDA) progression and poorer survival. Restoring STAG2 function may enhance patient response to platinum-based therapies, offering new treatment avenues for this lethal cancer.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer with complex genomic alterations.
- Identifying actionable somatic events in PDA is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the role of STAG2 in PDA development and progression.
- To assess STAG2 expression as a prognostic marker and therapeutic target in PDA.
Main Methods:
- Genomic profiling of PDA samples, including STAG2 sequencing and copy number analysis.
- In vivo studies using a KRAS (G12D)-driven mouse model to assess STAG2 disruption.
- Analysis of STAG2 protein expression in human PDA tissues and correlation with survival and treatment response.
- In vitro RNAi-mediated knockdown of STAG2 to evaluate drug sensitivity in PDA cell lines.
Main Results:
- Somatic aberrations targeting STAG2 occur in a subset of PDA patients (4%).
- STAG2 disruption in a mouse model promotes PDA development and metastasis.
- Loss of STAG2 protein expression is observed in human PDA tissues, correlating with poorer survival.
- STAG2 expression is an independent prognostic factor for PDA patient survival.
- STAG2 knockdown sensitizes PDA cells to platinum-based chemotherapy.
Conclusions:
- STAG2 acts as a clinically significant tumor suppressor in pancreatic ductal adenocarcinoma.
- STAG2 status may predict response to platinum-based therapies, suggesting its potential as a therapeutic target.
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