title: Very Long-term Survival Following Resection for Pancreatic Cancer Is Not Explained by Commonly Mutated Genes: Results of Whole-Exome Sequencing Analysis.
abstract: OBJECTIVE
  The median survival following surgical resection of pancreatic ductal adenocarcinoma (PDAC) is currently <20 months. However, survival ≥10 years is achieved by a small subset of patients who are defined as very long-term survivors (VLTS). The goal of this study was to determine whether specific genetic alterations in resected PDACs determined very long-term survival.
  
  
  METHODS
  We sequenced the exomes of eight PDACs from patients who survived ≥10 years. On the basis of the results of the exomic analysis, targeted sequencing of selected genes was performed in a series of 27 additional PDACs from VLTSs.
  
  
  RESULTS
  KRAS mutations were identified in 33 of 35 cancers (94%) from VLTSs and represented the most prevalent alteration in our cohort. TP53, SMAD4, and CDKN2A mutations occurred in 69%, 26%, and 17%, respectively. Mutations in RNF43, which have been previously associated with intraductal papillary mucinous neoplasms, were identified in four of the 35 cancers (11%). Taken together, our data show no difference in somatic mutations in carcinomas from VLTSs compared with available data from PDACs unselected for survival. Comparison of clinicopathologic features between VLTSs and a matching control group demonstrated that younger age, earlier stage, well/moderate grade of differentiation, and negative resection margins were associated with VLTS. However, more advanced stage, poor grade, or nodal disease did not preclude long-term survival.
  
  
  CONCLUSIONS
  Our results suggest that in most patients, somatic mutations in commonly mutated genes are unlikely to be the primary determinant of very long-term survival following surgical resection of PDAC.
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Marco
authors.initials: M
authors.lastname: Dal Molin
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Roeland F
authors.initials: RF
authors.lastname: de Wilde
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Niki A
authors.initials: NA
authors.lastname: Ottenhof
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Neda
authors.initials: N
authors.lastname: Rezaee
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Wolfgang
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Amanda
authors.initials: A
authors.lastname: Blackford
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Nickolas
authors.initials: N
authors.lastname: Papadopoulos
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.affiliation: Departments of Pathology and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. ldwood@jhmi.edu.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Wood
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000601:surgery; D016022:Case-Control Studies; D059472:Exome; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D059645:Mutation Rate; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology / Q000601:surgery / Q000628:therapy; D011379:Prognosis; D047368:Tumor Burden