title: Clinically relevant subsets identified by gene expression patterns support a revised ontogenic model of Wilms tumor: a Children's Oncology Group Study.
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.
authors.affiliation: Department of Pathology, Northwestern University's Feinberg School of Medicine and Robert H. Lurie Cancer Center, Chicago, IL, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Gadd
authors.forename: Vicki
authors.initials: V
authors.lastname: Huff
authors.forename: Chiang-Ching
authors.initials: CC
authors.lastname: Huang
authors.forename: E Cristy
authors.initials: EC
authors.lastname: Ruteshouser
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Dome
authors.forename: Paul E
authors.initials: PE
authors.lastname: Grundy
authors.forename: Norman
authors.initials: N
authors.lastname: Breslow
authors.forename: Lawrence
authors.initials: L
authors.lastname: Jennings
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Green
authors.forename: J Bruce
authors.initials: JB
authors.lastname: Beckwith
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Perlman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics*; D002471:Cell Transformation, Neoplastic; D002648:Child; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016162:Genes, Wilms Tumor; D006801:Humans; D007668:Kidney / Q000473:pathology; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019656:Loss of Heterozygosity; D009154:Mutation; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D025721:WT1 Proteins / Q000096:biosynthesis / Q000235:genetics*; D009396:Wilms Tumor / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051176:beta Catenin / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C517118:AMER1 protein, human; D048868:Adaptor Proteins, Signal Transducing; C495270:CTNNB1 protein, human; D025521:Tumor Suppressor Proteins; D025721:WT1 Proteins; D051176:beta Catenin