Transcriptional profiles in peripheral blood mononuclear cells prognostic of clinical outcomes in patients with advanced renal cell carcinoma.
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.
Burczynski
Michael E
ME
Molecular Profiling and Biomarker Discovery, Wyeth Research, 1 Burtt Road, Andover, MA 01810, USA. mburczynski@wyeth.com
Twine
Natalie C
NC
Dukart
Gary
G
Marshall
Bonnie
B
Hidalgo
Manuel
M
Stadler
Walter M
WM
Logan
Theodore
T
Dutcher
Janice
J
Hudes
Gary
G
Trepicchio
William L
WL
Strahs
Andrew
A
Immermann
Fred
F
Slonim
Donna K
DK
Dorner
Andrew J
AJ
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
D000903:Antibiotics, Antineoplastic; C401859:temsirolimus; D020123:Sirolimus