Clear cell renal cell carcinoma: gene expression analyses identify a potential signature for tumor aggressiveness.
OBJECTIVE
The objective of this study was to use gene expression profiling to identify novel biomarkers that are predictive of aggressive behavior in clear cell renal cell carcinoma (CCRCC).


METHODS
Candidate genes were discovered using Human Genome U133 Plus 2 Arrays and validated on independent samples by quantitative reverse transcription-PCR (RT-PCR). Both the discovery and the validation cohorts included nonaggressive primary CCRCC, aggressive primary CCRCC, metastatic CCRCC, and nonneoplastic kidney adjacent to tumor.


RESULTS
Aggressive primary and metastatic CCRCC displayed no significant differences in gene expression. In contrast, we identified significant differences in gene expression between nonaggressive and aggressive CCRCC (including metastatic CCRCC). Thirty-four of the 35 transcripts that displayed the most significant differential expression by microarray analysis also displayed significant differential expression in independent validation studies using quantitative RT-PCR (P < 0.001 for 31 candidates and P < 0.005 for the remaining three candidates). Hierarchical clustering of the quantitative RT-PCR data using our candidate markers accurately grouped 88% (23 of 26) of aggressive and metastatic CCRCC samples, 100% (14 of 14) of nonaggressive CCRCC samples, and 100% (15 of 15) of nonneoplastic samples into separate clusters. Finally, we evaluated the ability of protein expression levels of one of our candidate markers (survivin) to predict survival among a cohort of 183 CCRCC patients treated surgically at Mayo Clinic from 1990 to 1992. In multivariate analysis, expression of survivin (BIRC5) was inversely associated with cancer-specific survival (P = 0.017).


CONCLUSIONS
We used a combination of genomic profiling and validation by quantitative PCR to identify a panel of candidate biomarkers for determining CCRCC aggressiveness. Our data also indicate that the gene expression alterations that result in aggressive behavior and metastatic potential can be identified in the primary tumor.
Kosari
Farhad
F
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Parker
Alexander S
AS
Kube
Dagmar Marie
DM
Lohse
Christine M
CM
Leibovich
Bradley C
BC
Blute
Michael L
ML
Cheville
John C
JC
Vasmatzis
George
G
D014408:Biomarkers, Tumor / Q000032:analysis; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology*; D015331:Cohort Studies; D018450:Disease Progression; D020869:Gene Expression Profiling; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis
D014408:Biomarkers, Tumor