title: 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.
abstract: 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.
  
  
  
  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 next-generation sequencer, and the associations with clinicopathological factors were analyzed.
  
  
  
  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).
  
  
  
  The number of mutated driver genes assessed using a targeted deep sequencing assay was a promising prognostic biomarker for pancreatic cancer.
authors.affiliation: From the *Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo; †Division of Genome Biology, National Cancer Center Research Institute, Tokyo; ‡Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo; §Department of Cancer Chemotherapy, Hokkaido University Hospital Cancer Center, Sapporo; ∥Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo; Divisions of ¶Genetics and #Cancer Genomics, National Cancer Center Research Institute, Tokyo; and **Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Hayashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Kohno
authors.forename: Hideki
authors.initials: H
authors.lastname: Ueno
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Hiraoka
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kondo
authors.forename: Motonobu
authors.initials: M
authors.lastname: Saito
authors.forename: Yoko
authors.initials: Y
authors.lastname: Shimada
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ichikawa
authors.forename: Mamoru
authors.initials: M
authors.lastname: Kato
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shibata
authors.forename: Chigusa
authors.initials: C
authors.lastname: Morizane
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Sakamoto
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Shimada
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Komatsu
authors.forename: Naoya
authors.initials: N
authors.lastname: Sakamoto
authors.forename: Takuji
authors.initials: T
authors.lastname: Okusaka
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D003131:Combined Modality Therapy; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D015999:Multivariate Analysis; D009154:Mutation; D017063:Outcome Assessment, Health Care / Q000379:methods / Q000706:statistics & numerical data; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000601:surgery; D011379:Prognosis; D016016:Proportional Hazards Models; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D051901:Smad4 Protein / Q000235:genetics*; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; C117307:KRAS protein, human; D051901:Smad4 Protein; D016159:Tumor Suppressor Protein p53; D016283:Proto-Oncogene Proteins p21(ras)