Convergence for Inactivation of TGF-β 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 TGF-β pathway is a common feature of advanced-stage disease. However, SMAD4 inactivation is more common among de novo metastatic PDACs, whereas inactivation of TGF-β surface receptors is more common among locally advanced non-metastatic 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 radiated PDACs had significantly greater genomic complexity and distinct mutational signatures compared to 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.