TY - JOUR
T1 - Clinically relevant subsets identified by gene expression patterns support a revised ontogenic model of Wilms tumor
T2 - A Children's Oncology Group study
AU - Gadd, Samantha
AU - Huff, Vicki
AU - Huang, Chiang Ching
AU - Cristy Ruteshouser, E.
AU - Dome, Jeffrey S.
AU - Grundy, Paul E.
AU - Breslow, Norman
AU - Jennings, Lawrence
AU - Green, Daniel M.
AU - Bruce Beckwith, J.
AU - Perlman, Elizabeth J.
N1 - Funding Information:
Abbreviations: WT, Wilms tumor; ICR1, imprint control region 1; ICR2, imprint control region 2; MM, metanephric mesenchyme; LOI, loss of imprinting; LOH, loss of heterozygosity; ROI, retention of imprinting; UPD, uniparental disomy Address all correspondence to: Elizabeth J. Perlman, MD, Children’s Memorial Hospital, 2300 Children’s Plaza, Box 17, Chicago, IL 60614. E-mail: eperlman@childrensmemorial.org 1This work is supported by grants from the National Institutes of Health: U10CA42326 (N.B., D.M.G., E.J.P.). U10CA98543 ( J.S.D., P.E.G., E.J.P.), UO1CA88131 (E.J.P., C.C.H.), CA34936 (V.H.), DK069599 (V.H.), CA16672 (V.H.), RP100329 (V.H.), and RP110324 (V.H.). 2This article refers to supplementary materials, which are designated by Tables W1 and W2 and are available online at www.neoplasia.com. Received 23 April 2012; Revised 28 June 2012; Accepted 4 July 2012 Copyright © 2012 Neoplasia Press, Inc. All rights reserved 1522-8002/12/$25.00 DOI 10.1593/neo.12714
PY - 2012/8
Y1 - 2012/8
N2 - 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.
AB - 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.
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U2 - 10.1593/neo.12714
DO - 10.1593/neo.12714
M3 - Article
C2 - 22952427
AN - SCOPUS:84865245097
SN - 1522-8002
VL - 14
SP - 742
EP - 756
JO - Neoplasia (United States)
JF - Neoplasia (United States)
IS - 8
ER -