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

We performed WES of 250 unique tumor tissues from 30 multiregion sampled pancreatic cancer research autopsies from patients diagnosed with advanced stage disease. We find that most genetic alterations in PDAC occur in a subclonal manner, and some genes occurred in a subclonal manner exclusively. Convergent evolution within the TGFβ pathway was also identified as a common feature of advanced stage disease, with SMAD4 inactivation more common among metastatic PDACs compared to inactivation of TGFβ surface receptors that was more common in locally advanced tumors. The mode of clinical management (radiation versus chemotherapy) contributed distinct mutational signatures yet these mutations are not predicted to have functional relevance to tumor progression. Overall, these findings provide a first definition of the genetic features that distinguish among patients with locally advanced versus metastatic PDAC. These findings may have clinical relevance in upfront clinical decision making for the optimal candidates for neoadjuvant therapy. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was funded by the NIH/NCI grant R35 (CA220508-03) and U2C (CA233284-03) awarded to C.A.I-D. Cycle for Survival for David Rubenstein Center for Pancreatic Cancer Research. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Use of all human samples in this study was approved by the Institutional Review Board(IRB) at Memorial Sloan Kettering Cancer Center (under protocols #15-149, #15-021) and Johns Hopkins Medicine. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors