title: Clinical significance of the genetic landscape of pancreatic cancer and implications for identification of potential long-term survivors.
abstract: OBJECTIVE
  Genetic alterations of KRAS, CDKN2A, TP53, and SMAD4 are the most frequent events in pancreatic cancer. We determined the extent to which these 4 alterations are coexistent in the same carcinoma, and their impact on patient outcome.
  
  
  METHODS
  Pancreatic cancer patients who underwent an autopsy were studied (n = 79). Matched primary and metastasis tissues were evaluated for intragenic mutations in KRAS, CDKN2A, and TP53 and immunolabeled for CDKN2A, TP53, and SMAD4 protein products. The number of altered driver genes in each carcinoma was correlated to clinicopathologic features. Kaplan-Meier estimates were used to determine median disease free and overall survival, and a Cox proportional hazards model used to compare risk factors.
  
  
  RESULTS
  The number of genetically altered driver genes in a carcinoma was variable, with only 29 patients (37%) having an alteration in all 4 genes analyzed. The number of altered driver genes was significantly correlated with disease free survival (P = 0.008), overall survival (P = 0.041), and metastatic burden at autopsy (P = 0.002). On multivariate analysis, the number of driver gene alterations in a pancreatic carcinoma remained independently associated with overall survival (P = 0.046). Carcinomas with only 1 to 2 driver alterations were enriched for those patients with the longest survival (median 23 months, range 1 to 53).
  
  
  CONCLUSIONS
  Determinations of the status of the 4 major driver genes in pancreatic cancer, and specifically the extent to which they are coexistent in an individual patients cancer, provides distinct information regarding disease progression and survival that is independent of clinical stage and treatment status.
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Yachida
authors.forename: Catherine M
authors.initials: CM
authors.lastname: White
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Naito
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhong
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Brosnan
authors.forename: Anne M
authors.initials: AM
authors.lastname: Macgregor-Das
authors.forename: Richard A
authors.initials: RA
authors.lastname: Morgan
authors.forename: Tyler
authors.initials: T
authors.lastname: Saunders
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Laheru
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Herman
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.forename: Alison P
authors.initials: AP
authors.lastname: Klein
authors.forename: Siân
authors.initials: S
authors.lastname: Jones
authors.forename: Victor
authors.initials: V
authors.lastname: Velculescu
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Wolfgang
authors.forename: Christine A
authors.initials: CA
authors.lastname: Iacobuzio-Donahue
mesh_terms: D000368:Aged; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012307:Risk Factors; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism; D017741:Survivors; D047368:Tumor Burden / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins