Abstract 5353: Comprehensive Ggnomic analysis of diffuse hyperplastic perilobar nephroblastomatosis (DHPLN)
Authors: Gadd Samantha L. , Huang Chiang-Ching , Lu Yiling , Huff Vicki , Perlman Elizabeth J. 
Published: June 2012

Abstract
Background: Wilms tumors (WT) commonly arise in the setting of precursor lesions known as nephrogenic rests. DHPLN is characterized by a continuous rind-like involvement of all or part of the kidney by nephrogenic rest. Patients with DHPLN are often difficult to manage clinically. This study investigates DHPLN in order to better understand the pathogenesis and to determine potential therapeutic targets.
Methods: Five DHPLN were compared with 5 WT that developed from perilobar nephrogenic rests and with 3 fetal kidney samples. The following platforms were used: Illumina Human 610-Quad Beadchip, Affymetrix U133 plus 2 arrays, Illumina Infinium Human Methylation 27 DNA Analysis BeadChip, Illumina 96-sample Universal Matrix Array for miRNA analysis. In addition, key signaling pathway component analysis was performed using Reverse Phase Protein Array (RPPA) analysis. Lastly, we compared the gene expression of the above samples with 242 WT samples previously reported.
Results: The five DHPLN samples showed 1, 1, 2, 3, and 10 small regions of low-level gain or loss. In contrast, the WT samples all showed larger and more numerous areas of gain or loss. The normal copy number for loci on chromosome 11p was present in all DHPLNs, although 2/5 showed allelic imbalance of distal 11p, consistent with uniparental isodisomy, confirmed by methylation analysis of H19DMR and KvDMR1. The remaining 3 DHPLN showed loss of imprinting with 100% methylation of H19DMR. The gene expression of several key inhibitors of the Wnt pathway were upregulated in DHPLN (Axin-10 GSK-3, WISP3, and APC). TCF21 (POD1), a potential tumor suppressor gene, was down-regulated in DHPLN compared with fetal kidney. Lastly, PLAG1, a transcription factor that positively regulates IGF2, was highly elevated in fetal kidney, down-regulated in DHPLN, and upregulated in most WT. Several significant genes were shown to be both highly methylated and down-regulated, including TCF21, and the Wnt-related genes ITGA6, SFRP1, and PLAGL2. Significantly increased expression of miRNAs overall was identified within DHPLN compared with WT, including the Let-7 miRNA cluster. Upregulation of miR135 may be the mechanism for down-regulation of PLAG1 in DHPLN. Finally, RPPA revealed up-regulation of multiple members of the mTOR pathway in both DHPLN and WT compared with fetal kidney.
Conclusions: This data suggests the following hypotheses: DHPLN may arise due to biallelic expression of IGF2. Down-regulation of TCF21 may contribute to the formation of DHPLN. Clonal increased expression of PLAG1 may contribute to the development of WT within DHPLN. Potential therapeutic targets for both DHPLN and Wilms tumors developing with DHPLN include mTOR inhibitors and related cyclin-D1 inhibitors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5353. doi:10.1158/1538-7445.AM2011-5353