Somatic Mutation Profiling in the Liquid Biopsy and Clinical Analysis of Hereditary and Familial Pancreatic Cancer Cases Reveals KRAS Negativity and a Longer Overall Survival

© 2021 by the authors.Pancreatic ductal adenocarcinoma (PDAC) presents many challenges in the clinic and there are many areas for improvement in diagnostics and patient management. The five-year survival rate is around 7.2% as the majority of patients present with advanced disease at diagnosis that is treatment resistant. Approximately 10–15% of PDAC cases have a hereditary basis or Familial Pancreatic Cancer (FPC). Here we demonstrate the use of circulating free DNA (cfDNA) in plasma as a prognostic biomarker in PDAC. The levels of cfDNA correlated with disease status, disease stage, and overall survival. Furthermore, we show for the first time via BEAMing that the majority of hereditary or familial PDAC cases (around 84%) are negative for a KRAS somatic mutation. In addition, KRAS mutation negative cases harbor somatic mutations in potentially druggable genes such as KIT, PDGFR, MET, BRAF, and PIK3CA that could be exploited in the clinic. Finally, familial or hereditary cases have a longer overall survival compared to sporadic cases (10.2 vs. 21.7 months, respectively). Currently, all patients are treated the same in the clinic with cytotoxic agents, although here we demonstrate that there are different subtypes of tumors at the genetic level that could pave the way to personalized treatment.This study was funded by the Instituto de Salud Carlos III (Plan Estatal de I+D+i 2013– 2016): ISCIII (PI09/02221, PI12/01635, PI15/02101, and PI18/0135) and co-financed by the European Development Regional Fund “A way to achieve Europe” (ERDF), the Biomedical Research Network in Cancer: CIBERONC (CB16/12/00446), Red Temática de investigación cooperativa en cáncer: RTICC (RD12/0036/0073), La Asociación Española contra el Cáncer: AECC (Grupos Coordinados Estables 2016), Fundación Mutua Madrileña (FMM) / XVI Convocatoria de Ayudas a la Investigación en Salud 2019 and Asociación Cáncer de Páncreas (ACanPan); Asociación Española de Pancreatología (AESPANC) / IV Becas de Investigación Carmen Delgado/Miguel Pérez-Mateo 2019. The European Union’s Horizon 2020 research and innovation program under grant agreement No 857381, project VISION (Strategies to strengthen scientific excellence and innovation capacity for early diagnosis of gastrointestinal cancers).Peer reviewe