Subsets of Very Low Risk Wilms Tumor Show Distinctive Gene Expression, Histologic, and Clinical Features

Abstract

Purpose: Recent studies suggest that children <24 months with stage I favorable histology Wilms tumors <550 g [very low risk Wilms tumors (VLRWT)] have an excellent prognosis when treated with nephrectomy only, without adjuvant chemotherapy. The identification of risk categories within VLRWT may enable refinement of their definition and optimization of their therapy. Experimental Design: To define biologically distinct subsets, global gene expression analysis was done on 39 VLRWT that passed all quality-control parameters and the clusters identified were validated in an independent set of 11 VLRWT. Validation of select differentially expressed genes was done with immunohistochemistry on a tissue microarray from 20 of 39 tumors. Loss of heterozygosity (LOH) for 11p15, 1p, and 16q was analyzed in 52 tumors using PCR. Results: Two distinctive clusters were identified. One cluster included 9 tumors with epithelial differentiated tubular histology, paucity of nephrogenic rests, lack of LOH for 1p, 16q, and 11p, absence of relapse, and a unique gene expression profile consistent with arrest following mesenchymal-to-epithelial transition. The second cluster included 13 tumors with mixed histology, intralobar nephrogenic rests, and decreased expression of WT1. Three of 6 relapses occurred in this cluster. Of 43 informative tumors, 11p LOH was present in 5 of 5 relapses and 11 of 38 nonrelapses. Conclusions: Two subsets comprising a total of 56% of VLRWT are identified that have pathogenetic and molecular differences and apparent differences in risk for relapse. If these predictors can be prospectively validated, this would enable the refinement of clinical stratification and less arbitrary definition of VLRWT. ( A retrospective analysis of children treated on the first three National Wilms Tumor Study (NWTS) protocols supported this hypothesis by noting that changes in the NWTS treatment regimens over a period of >20 years have not improved on the excellent prognosis of this group of patients (2). The first prospective cooperative group evaluation of nephrectomy as the only treatment for VLRWT was initiated in 1995 within NWTS-5, which registered 75 eligible patients. Eight patients recurred and 3 developed metachronous contralateral tumors, resulting in a 2-year disease-free survival estimate of 86.5% (3). Due to preestablished stopping rules, this therapeutic arm was closed and patients previously registered were given the option of receiving chemotherapy late in their course. Following this closure, NWTS-5 patients meeting the criteria for VLRWT were

Lim1, an Embryonal Transcription Factor, Is Absent in Multicystic Renal Dysplasia, but Reactivated in Nephroblastomas

“…In one patient with MayerRokitansky-Kuster-Hauser syndrome showing bilateral multicystic dysplastic kidneys a microdeletion at chromosome 17q12 has been detected that includes among role of LIM1 in the pathogenesis of nephroblastomas has not been investigated in detail to date. Microarray analysis of a xenograft model of nephroblastomas [28] and an additional microarray analysis of various subtypes of primary nephroblastomas indicated that overexpression of LIM1 might play a role in their pathogenesis [13,28] . In our series of various subtypes of nephroblastomas only 1 of 12 samples with LIM1 expression showed diffuse staining in tubular structures.…”

“…Several transcription factors that are active during renal development have also been found to be reactivated in nephroblastomas. These include HMGA2 (high mobility group AT-hook 2) [13] , CITED1 [2] and PAX2 [3] . Despite the already described overexpression of PAX2 in nephroblastomas in blastema and some epithelial structures by in situ hybridization [3] and in the epithelial component by Western blot and immunohistochemistry [27] , surprisingly the Additionally, we evaluated more common renal neoplasms, clear cell carcinomas and papillary cell carcinomas of the kidney, for expression of LIM1 .…”

“…The reason of hydronephrosis seems to be vesicoureteral reflux comparable in morphology and pathogenetic mechanism with humans suffering from this disease [11] . So far, the role of LIM1 in human disease has hardly been investigated [12] , only one recent study using microarray analysis indicated overexpression of LIM1 in a subset of nephroblastomas [13] .…”

Network-based interactive navigation and analysis of large biological datasets

“…In our case study we consider the GSE14767 gene expression dataset [35] from the GEO repository comprising 39 microarray measurements of Wilms tumor samples. A Wilms tumor is a kind of kidney cancer which mainly affects children and contains metanephric blastema.…”

“…Tumors with a high level of epithelial differentiation (EDT) have been reported to be associated with very good survival rates. On the other hand tumors containing higher amounts of metanephric blastema (blastemal tumors) have a much worse prognosis with a 79% chance of the tumor reappearing after four years [35]. Here we want to study the differences between blastemal tumors as sample and EDT as reference group.…”