Clinically relevant subsets identified by gene expression patterns support a revised ontogenic model of Wilms tumor: a Children's Oncology Group Study - PubMed (original) (raw)

Clinically relevant subsets identified by gene expression patterns support a revised ontogenic model of Wilms tumor: a Children's Oncology Group Study

Samantha Gadd et al. Neoplasia. 2012 Aug.

Abstract

Wilms tumors (WT) have provided broad insights into the interface between development and tumorigenesis. Further understanding is confounded by their genetic, histologic, and clinical heterogeneity, the basis of which remains largely unknown. We evaluated 224 WT for global gene expression patterns; WT1, CTNNB1, and WTX mutation; and 11p15 copy number and methylation patterns. Five subsets were identified showing distinct differences in their pathologic and clinical features: these findings were validated in 100 additional WT. The gene expression pattern of each subset was compared with published gene expression profiles during normal renal development. A novel subset of epithelial WT in infants lacked WT1, CTNNB1, and WTX mutations and nephrogenic rests and displayed a gene expression pattern of the postinduction nephron, and none recurred. Three subsets were characterized by a low expression of WT1 and intralobar nephrogenic rests. These differed in their frequency of WT1 and CTNNB1 mutations, in their age, in their relapse rate, and in their expression similarities with the intermediate mesoderm versus the metanephric mesenchyme. The largest subset was characterized by biallelic methylation of the imprint control region 1, a gene expression profile of the metanephric mesenchyme, and both interlunar and perilobar nephrogenic rests. These data provide a biologic explanation for the clinical and pathologic heterogeneity seen within WT and enable the future development of subset-specific therapeutic strategies. Further, these data support a revision of the current model of WT ontogeny, which allows for an interplay between the type of initiating event and the developmental stage in which it occurs.

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Figures

Figure 1

Figure 1

Hierarchical analysis of 224 FHWT: (A) Unsupervised hierarchical analysis using the 4000 probe sets with the highest coefficient of variation. Two subsets are designated by the blue (S1) and red bars (S2). Also shown are the tumors identified in B in green (S3) and purple (S4). Tumors that relapsed are designated in red at the top of the dendrogram. Expression of genes, clustered on the y axis, is shown with levels ranging from high (red) to low (green). The expressions of the two WT1 probe sets are illustrated separately at the bottom. Four tumors outside S1 that show solely epithelial tubular differentiation are marked with a red asterisk. See Table W1 for the top 100 genes differentially expressed in S1 to S4 compared with S5. (B) Hierarchical analysis using the 54 genes with a Pearson correlation coefficient greater than 0.60 or less than -0.60 for both available WT1 alleles. S1 and S2 are readily identified (blue and red bars). Two additional subsets are now apparent, indicated by green (S3) and purple bars (S4). Genes associated with muscle differentiation are marked. (C) Hierarchical analysis of Wnt targets with a coefficient of variation greater than 0.06. S1 (blue) and S2 (red) clustered tightly together. Tumors in S3 (green) and S4 (purple) did not show evidence of strong Wnt activation and did not cluster.

Figure 2

Figure 2

Patterns of gene expression within the different subsets of FHWT: The log expression levels (low to high) of selected genes are plotted on the y axis. The x axis reflects an arbitrary tumor number, grouping the different tumor types starting with S1 in blue, followed S2 in red, S3 in green, S4 in purple, and the remaining tumors (S5) in turquoise.

Figure 3

Figure 3

11p15 methylation and subset validation. (A) ICR1 and ICR2 methylation: Three patterns of methylation were identified: 11p15 LOH (80%–100% methylation of ICR1 and 0%–20% methylation of ICR2), 11p15 LOI (80%–100% methylation of ICR1 and 30%–70% methylation of ICR2), and 11p15 ROI (30%–70% methylation of both ICR1 and ICR2). Tumors with values outside these ranges were not classified. (B) Validation with an independent set of 100 FHWT: Hierarchical analysis was performed using the top genes from Table W1. This demonstrates three subsets of FHWT with the same clinical and pathologic features of S1, S2, and S3 of the training set.

Figure 4

Figure 4

Revised model for WT ontogeny. See text for description.

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