title: Integrative survival-based molecular profiling of human pancreatic cancer.
abstract: OBJECTIVE
  To carry out an integrative profile of human pancreatic ductal adenocarcinoma (PDAC) to identify prognosis-significant genes and their related pathways.
  
  
  METHODS
  A concordant survival-based whole genome in silico array analysis of DNA copy number, and mRNA and miRNA expression in 25 early-stage PDAC was carried out. A novel composite score simultaneously integrated gene expression with regulatory mechanisms to identify the signature genes with the most levels of prognosis-significant evidence. The predominant signaling pathways were determined via a pathway-based approach. Independent patient cohorts (n = 148 and 42) were then used as in vitro validation of the array findings.
  
  
  RESULTS
  The composite score identified 171 genes in which expressions were able to define two prognosis subgroups (P = 3.8e-5). Eighty-eight percent (151 of 171) of the genes were regulated by prognosis-significant miRNAs. The phosphoinositide 3-kinase/AKT pathway and SRC signaling were densely populated by prognosis-significant genes and driven by genomic amplification of SRC and miRNA regulation of p85α and CBL. On tissue microarray validation (n = 148), p85α protein expression was associated with improved survival for all patients (P = 0.02), and activated P-SRC (Y418) was associated shorter survival for patients with low-grade histology tumors (P = 0.04). Interacting P-SRC and p85α revealed that they define two distinct PDAC patient subgroups (P = 0.0066). Furthering the importance of these pathways, CBL protein expression was associated with improved survival (P = 0.03) on a separate cohort (n = 42).
  
  
  CONCLUSIONS
  These pathways and related genes may represent putative clinical biomarkers and possible targets of individualized therapy in the distinct patient subgroups they define.
authors.affiliation: Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA. tdonahue@mednet.ucla.edu
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Donahue
authors.forename: Linh M
authors.initials: LM
authors.lastname: Tran
authors.forename: Reginald
authors.initials: R
authors.lastname: Hill
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Li
authors.forename: Anne
authors.initials: A
authors.lastname: Kovochich
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Calvopina
authors.forename: Sanjeet G
authors.initials: SG
authors.lastname: Patel
authors.forename: Nanping
authors.initials: N
authors.lastname: Wu
authors.forename: Antreas
authors.initials: A
authors.lastname: Hindoyan
authors.forename: James J
authors.initials: JJ
authors.lastname: Farrell
authors.forename: Xinmin
authors.initials: X
authors.lastname: Li
authors.forename: David W
authors.initials: DW
authors.lastname: Dawson
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000401:mortality*; D016000:Cluster Analysis; D056915:DNA Copy Number Variations; D005260:Female; D020869:Gene Expression Profiling; D023281:Genomics; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000401:mortality*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D015203:Reproducibility of Results; D015398:Signal Transduction; D016019:Survival Analysis; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases