Integrative survival-based molecular profiling of human pancreatic cancer.
Clin Cancer Res, 2012/3/01;18(5):1352-63.
Donahue TR[1], Tran LM, Hill R, Li Y, Kovochich A, Calvopina JH, Patel SG, Wu N, Hindoyan A, Farrell JJ, Li X, Dawson DW, Wu H
Affiliations
PMID: 22261810DOI: 10.1158/1078-0432.CCR-11-1539
Impact factor: 13.801
Abstract
purpose: To carry out an integrative profile of human pancreatic ductal adenocarcinoma (PDAC) to identify prognosis-significant genes and their related pathways.
experimental design: 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.
MeSH terms
Aged; Aged, 80 and over; Carcinoma, Pancreatic Ductal; Cluster Analysis; DNA Copy Number Variations; Female; Gene Expression Profiling; Genomics; Humans; Male; MicroRNAs; Middle Aged; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Prognosis; RNA, Messenger; Reproducibility of Results; Signal Transduction; Survival Analysis; src-Family Kinases
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