Abstract A045: Transcriptional evidence of IPMN-lineage differentiation in GNAS- and RNF43-mutant pancreatic adenocarcinoma
Krity Basnet, Ecem Kalemoglu, Priyank ChokshiAbstract
Background:
GNAS and RNF43 mutations are characteristic molecular alterations of intraductal papillary mucinous neoplasms (IPMNs), a recognized precursor lesion of pancreatic adenocarcinoma. While IPMNs are clinically and histologically distinct from conventional pancreatic ductal adenocarcinoma (PDAC), the transcriptomic identity of invasive pancreatic adenocarcinomas harboring these mutations remains incompletely defined. We hypothesized that pancreatic adenocarcinomas with GNAS and/or RNF43 alterations retain a transcriptional signature consistent with IPMN-lineage differentiation, even after progression to invasive carcinoma.
Methods:
We analyzed tumors from The Cancer Genome Atlas Pancreatic Adenocarcinoma (TCGA-PAAD) cohort with available somatic mutation and RNA-sequencing data. Cases harboring GNAS and/or RNF43 mutations were classified as IPMN-like, while tumors lacking these alterations served as comparators. Differential gene expression analysis was performed between groups using established bioinformatic pipelines, followed by Hallmark gene set enrichment analysis. A composite IPMN differentiation score was constructed from genes associated with intestinal-mucinous IPMN lineage and compared across groups. Clinicopathologic features including tumor stage, metastatic status, and survival outcomes were also evaluated.
Results:
Among 177 mutation-profiled pancreatic adenocarcinomas, 18 tumors (10.2%) demonstrated an IPMN-like molecular genotype defined by GNAS and/or RNF43 mutation. Clinical stage, metastatic status, and survival outcomes were similar between groups. Differential expression analysis identified 46 significantly dysregulated genes at a false discovery rate (FDR) <0.05. IPMN-like tumors exhibited increased expression of intestinal differentiation markers including SPINK4, TFF3, MUC2, and MUC5AC. Gene set enrichment analysis revealed relative suppression of KRAS signaling (NES -1.69, FDR 0.0002), inflammatory response (NES -1.48, FDR 0.019), epithelial-mesenchymal transition (NES -1.44, FDR 0.023), and apical junction signaling (NES -1.36, FDR 0.049). A composite IPMN differentiation score was significantly elevated in GNAS/RNF43-mutant tumors (p=0.00034).
Conclusions:
Pancreatic adenocarcinomas harboring GNAS and/or RNF43 mutations retain a transcriptional program consistent with intestinal-mucinous IPMN differentiation, despite clinical outcomes similar to conventional PDAC. These findings support the existence of a molecularly distinct biologic lineage within invasive pancreatic adenocarcinoma. Mutation-defined IPMN-like carcinomas remain transcriptionally recognizable after invasion, suggesting that precursor lineage imprints durable gene expression patterns. Future studies should explore whether this transcriptional phenotype influences therapeutic response.
Citation Format:
Krity Basnet, Ecem Kalemoglu, Priyank Chokshi. Transcriptional evidence of IPMN-lineage differentiation in GNAS- and RNF43-mutant pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr A045.