title: Transcriptional profiles in peripheral blood mononuclear cells prognostic of clinical outcomes in patients with advanced renal cell carcinoma.
abstract: OBJECTIVE
  Given their accessibility, surrogate tissues, such as peripheral blood mononuclear cells (PBMC), may provide potential predictive biomarkers in clinical pharmacogenomic studies. In leukemias and lymphomas, the prognostic value of peripheral blast expression profiles is clear; however, it is unclear whether circulating mononuclear cells of patients with solid tumors might yield profiles with similar prognostic associations.
  
  
  METHODS
  In this study, we evaluated the association of expression profiles in PBMCs with clinical outcomes in patients with advanced renal cell cancer. Transcriptional patterns in PBMCs of 45 renal cell cancer patients were compared with clinical outcome data at the conclusion of a phase II study of the mTOR kinase inhibitor CCI-779 to determine whether pretreatment transcriptional patterns in PBMCs were correlated with eventual patient outcomes.
  
  
  RESULTS
  Unsupervised hierarchical clustering of the PBMC profiles using all expressed genes identified clusters of patients with significant differences in survival. Cox proportional hazards modeling showed that the expression levels of many PBMC transcripts were predictors for the patient outcomes of time to progression and overall survival (time to death). Supervised class prediction approaches identified multivariate expression patterns in PBMCs capable of assigning favorable outcomes of time to death and time to progression in a test set of renal cancer patients, with overall performance accuracies of 72% and 85%, respectively.
  
  
  CONCLUSIONS
  The present study provides the first example of gene expression profiling in peripheral blood, a clinically accessible surrogate tissue, for identifying patterns of gene expression associated with higher likelihoods of positive outcome in patients with a solid tumor.
authors.affiliation: Molecular Profiling and Biomarker Discovery, Wyeth Research, 1 Burtt Road, Andover, MA 01810, USA. mburczynski@wyeth.com
authors.forename: Michael E
authors.initials: ME
authors.lastname: Burczynski
authors.forename: Natalie C
authors.initials: NC
authors.lastname: Twine
authors.forename: Gary
authors.initials: G
authors.lastname: Dukart
authors.forename: Bonnie
authors.initials: B
authors.lastname: Marshall
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
authors.forename: Walter M
authors.initials: WM
authors.lastname: Stadler
authors.forename: Theodore
authors.initials: T
authors.lastname: Logan
authors.forename: Janice
authors.initials: J
authors.lastname: Dutcher
authors.forename: Gary
authors.initials: G
authors.lastname: Hudes
authors.forename: William L
authors.initials: WL
authors.lastname: Trepicchio
authors.forename: Andrew
authors.initials: A
authors.lastname: Strahs
authors.forename: Fred
authors.initials: F
authors.lastname: Immermann
authors.forename: Donna K
authors.initials: DK
authors.lastname: Slonim
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Dorner
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016019:Survival Analysis; D014158:Transcription, Genetic / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D000903:Antibiotics, Antineoplastic; C401859:temsirolimus; D020123:Sirolimus