Clinicopathological and molecular characterization of <scp><i>KRAS</i></scp> wild‐type pancreatic ductal adenocarcinomas reveals precursor lesions with oncogenic mutations and fusions in <scp>RAS</scp> pathway genes

Pancreatic ductal adenocarcinomas (PDACs) with wild-type KRAS constitute a small fraction of PDACs, and these tumors were recently shown to harbor frequent actionable oncogenic mutations and fusions. However, the clinicopathological features of KRAS wild-type PDAC have not been well studied. Additionally, precancerous lesions occurring in patients with KRAS wild-type PDACs have rarely been characterized. Here, we investigated the clinicopathological characteristics and outcomes of 75 patients with KRAS wild-type PDAC. Molecular analyses were performed in 40 patients using targeted DNA and whole-exome sequencing and targeted RNA sequencing. We demonstrated that patients with metastatic PDAC with wild-type KRAS were younger (median 59.5 years) than those with mutated KRAS (median 67 years, p < 0.000055). The wild-type KRAS status was not a significant prognostic factor for metastatic disease. Molecularly, genes in the RAS pathway are frequently mutated or rearranged (46%, 16/35), including mutations in BRAF, NRAS, HRAS, EGFR, MAP2K1, FGFR1, FGFR3 and ERBB4 and fusions of FGFR2 (FGFR2::CCDC147, FGFR2::CAT, FGFR2::TXLNA), ALK (STRN::ALK, EML4::ALK), and BRAF (TRIP11::BRAF). Mismatch repair deficiency was identified in 10% (4/39) of patients. Potentially actionable alterations were identified frequently in KRAS wild-type PDACs (30%, 12/40), in which nontubular-type carcinomas were significantly enriched with actionable alterations compared with tubular adenocarcinomas [67% (6/9) versus 16% (5/31); p = 0.007]. Finally, we investigated the precursors of PDACs in 13 pancreatectomy specimens from patients with KRAS wild-type PDAC. We identified three pancreatic intraepithelial neoplasias (PanINs) and two intraductal papillary mucinous neoplasms (IPMNs) harboring oncogenic fusions of ALK and BRAF and driver mutations in BRAF and AKT1. This study suggests that in the context of unmutated KRAS, PDAC is driven by alternative oncogenic mutations or fusions of RAS pathway genes, which may be introduced during the early phase of tumorigenesis. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.