AbstractBackgroundApproximately 90% of pancreatic ductal adenocarcinoma (PDAC) cases are driven by the untargetable non‐G12CKRASmutations, and only a small subset of patients are eligible for FDA‐approved precision therapies. The practice of precision therapy in pancreatic cancer was limited by the paucity of targetable genetic alterations, especially in the Asian population.MethodsTo explore therapeutic targets in 499 Chinese PDAC patients, a deep sequencing panel (OncoPanscan™, Genetron health) was used to characterize somatic alterations including point mutations, indels, copy number alterations, gene fusions as well as pathogenic germline variants.ResultsWe performed genomic profiling in 499 Chinese PDAC patients, which revealed somatic driver mutations inKRAS,TP53,CDKN2A,SMAD4,ARID1A,RNF43, and pathogenic germline variants (PGVs) in cancer predisposition genes includingBRCA2,PALB2, andATM. Overall, 20.4% of patients had targetable genomic alterations. About 8.4% of patients carried inactivating germline and somatic variants inBRCA1/2andPALB2, which were susceptible to platinum and PARP inhibitors therapy. Patients withKRASwild‐type disease and early‐onset pancreatic cancer (EOPC) harbored actionable mutations includingBRAF,EGFR,ERBB2, andMAP2K1/2. Compared to PGV‐negative patients, PGV‐positive patients were younger and more likely to have a family history of cancer. Furthermore, PGVs inPALB2,BRCA2, andATMwere associated with high PDAC risk in the Chinese population.ConclusionsOur results demonstrated that a genetic screen of actionable genomic variants could facilitate precision therapy and cancer risk reduction in pancreatic cancer patients of Asian ethnicity.