Predicting relapse in favorable histology Wilms tumor using gene expression analysis: a report from the Renal Tumor Committee of the Children's Oncology Group.
OBJECTIVE
The past two decades has seen significant improvement in the overall survival of patients with favorable histology Wilms tumor (FHWT); however, this progress has reached a plateau. Further improvements may rely on the ability to better stratify patients by risk of relapse. This study determines the feasibility and potential clinical utility of classifiers of relapse based on global gene expression analysis.


METHODS
Two hundred fifty FHWT of all stages enriched for relapses treated on National Wilms Tumor Study-5 passed quality variables and were suitable for analysis using oligonucleotide arrays. Relapse risk stratification used support vector machine; 2- and 10-fold cross-validations were applied.


RESULTS
The number of genes associated with relapse was less than that predicted by chance alone for 106 patients (32 relapses) with stages I and II FHWT treated with chemotherapy, and no further analyses were done. This number was greater than expected by chance for 76 local stage III patients. Cross-validation including an additional 68 local stage III patients (total 144 patients, 53 relapses) showed that classifiers for relapse composed of 50 genes were associated with a median sensitivity of 47% and specificity of 70%.


CONCLUSIONS
This study shows the feasibility and modest accuracy of stratifying local stage III FHWT using a classifier of <50 genes. Validation using an independent patient population is needed. Analysis of genes differentially expressed in relapse patients revealed apoptosis, Wnt signaling, insulin-like growth factor pathway, and epigenetic modification to be mechanisms important in relapse. Potential therapeutic targets include FRAP/MTOR and CD40.
Huang
Chiang-Ching
CC
Department of Preventive Medicine, Northwestern University's Feinberg School of Medicine and Robert H. Lurie Cancer Center, Chicago, Illinois 60614, USA.
Gadd
Samantha
S
Breslow
Norman
N
Cutcliffe
Colleen
C
Sredni
Simone T
ST
Helenowski
Irene B
IB
Dome
Jeffrey S
JS
Grundy
Paul E
PE
Green
Daniel M
DM
Fritsch
Michael K
MK
Perlman
Elizabeth J
EJ
D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002648:Child; D005240:Feasibility Studies; D020869:Gene Expression Profiling; D006801:Humans; D007680:Kidney Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000556:secondary; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000235:genetics; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D009396:Wilms Tumor / Q000175:diagnosis* / Q000235:genetics
D014408:Biomarkers, Tumor