Utility of Assessing the Number of Mutated KRAS, CDKN2A, TP53, and SMAD4 Genes Using a Targeted Deep Sequencing Assay as a Prognostic Biomarker for Pancreatic Cancer

Objectives: KRAS, CDKN2A, TP53, and SMAD4 have been recognized as major driver genes in pancreatic carcinogenesis. We examined somatic mutations in 50 cancer- related genes, including the four above-mentioned driver genes, to identify genomic biomarkers for predicting the outcome of patients with pancreatic cancer. Methods: Genomic DNA was extracted from fresh-frozen specimens obtained from 100 patients with pancreatic cancer who had undergone a pancreatectomy with curative intent. The mutation profile was obtained using a single targeted deep sequencing assay performed with a nextgeneration sequencer, and the associations with clinicopathological factors were analyzed. Results: Mutations in the KRAS, CDKN2A, TP53, and SMAD4 genes were detected in 96% (96/100), 42% (42/100), 13% (13/100), and 7% (7/100) of all patients, respectively. Among the 71 patients who underwent a radical operation followed by adjuvant chemotherapy, patients with fewer mutations among the four driver genes tended to have a better outcome. A multivariate analysis using the Cox proportional hazard model showed that the presence of 0 to 2 mutated driver genes was an independent predictor of a better overall survival (hazard ratio for death, 0.20; P = 0.0040). Conclusions: The number of mutated driver genes assessed using a targeted deep sequencing assay was a promising prognostic biomarker for pancreatic cancer.