Convergence for Inactivation of TGFβ Signaling Is a Common Feature of Advanced Pancreatic Cancer

We performed whole-exome sequencing of 250 unique tumor tissues from 30 multi-region sampled pancreatic cancer research autopsies from patients diagnosed with advanced-stage disease. Convergent evolution within the TGFβ pathway is a common feature of advanced-stage disease. However, SMAD4 inactivation is more common among de novo metastatic pancreatic ductal adenocarcinomas (PDAC), whereas inactivation of TGFβ surface receptors is more common among locally advanced nonmetastatic cancers. These differences in metastatic propensity were orthogonally validated in mice by orthotopic injections of PDAC organoids with SMAD4 versus TGFBR2 inactivation. No functionally deleterious driver gene mutations were identified that were attributed to treatment, although irradiated PDACs had significantly greater genomic complexity and distinct mutational signatures compared with PDACs managed by chemotherapy. These findings provide a high-level profile of the genetic features distinguishing locally advanced from metastatic PDAC, potentially serving as a biomarker of borderline resectable or locally advanced PDACs most likely to benefit from neoadjuvant chemoradiation. SIGNIFICANCE: This study fills an important gap in knowledge related to the characteristics of genomic alterations of advanced-stage disease. We expect that these findings will serve as a baseline reference set to identify mechanisms of resistance as novel therapies continue to become available for patients with PDAC.