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Gene Expression Profiling of Favorable Histology Wilms Tumors and Its Correlation with Clinical Features

Laboratory of Cancer Genetics [M. Ta., T. T. L., B. T. T.], Bioinformatics Program [K. A. F.], and Laboratory of Cell Signaling and Carcinogenesis [B. O. W.], Van Andel Research Institute, Grand Rapids, Michigan 49503; Department of Urology, School of Medicine, The University of Tokushima, Tokushima 770-8503, Japan [M. Ta., S. K.]; Departments of Pathology [X. J. Y., M. Tr., A. M.], Medicine [N. J. V.], Surgery [X. J. Y., A. M., N. J. V.], University of Chicago Cancer Research Center, Chicago, Illinois 60637; Department of Pathology and Laboratory Medicine [G. G. R., D. H-M.], Medical University of South Carolina, Charleston, South Carolina 29425; Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157 [A. J. G.]; and Department of Women and Child Health [S. S.] and Department of Molecular Medicine, Department of Women and Child Health [A. N.], Astrid Lindgren Children Hospital, Karolinska Hospital, Stockholm 17176, Sweden

The aims of this study were to understand the underlying molecular mechanisms of favorable histology Wilms tumors (WTs) and to classify them based on their molecular signatures. We studied a total of 15 favorable histology WTs using microarrays containing 19,968 cDNAs. First, we found commonly altered genes in WT. A total of 267 cDNAs were significantly overexpressed at least 3-fold in all of the tumors compared with noncancerous kidney and contained known WT-related genes such as IGF II and WT1. The gene with the highest expression change compared with noncancerous kidney was topoisomerase II. By hierarchical clustering, there was a clear distinction between high-stage and low-stage tumors. A total of 30 cDNAs were found differentially expressed between the high- and low-stage groups. One of them, Stathmin 1, which is involved in the microtubule system, was highly expressed in high-stage tumors compared with the low-stage tumors. The present chemotherapy regimens for WT consist mainly of topoisomerase II inhibitors (i.e., actinomycin D, doxorubicin, and etoposide) and antimicrotubule agents (i.e., vincristine and paclitaxel). Our data suggest that high expression of topoisomerase II and microtubule-related genes such as tubulin and stathmin 1 may be related to the high chemosensitivity of WT. In addition, retinol-related genes such as CRABP2 and retinol-binding protein 1 were overexpressed in WT, and CRABP2 was more highly expressed in the poor outcome patients, which suggests that retinoid acid may be a potential drug. In summary, our findings suggest that the integration of gene expression data and clinical parameters could aid in detecting aggressive tumors among favorable histology WT and lead to the discovery of new drugs for WT.

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