Affiliations of authors: I. M. Morison, A. E. Reeve, Cancer Genetics Laboratory, Department of Biochemistry, University of Otago, Dunedin, New Zealand; D. M. O. Becroft, Department of Obstetrics and Gynaecology, University of Auckland, Auckland, New Zealand.
Corresponding author: Ian M. Morison, M.B., Ch.B., Ph.D., Cancer Genetics Laboratory, Department of Biochemistry, University of Otago, P.O. Box 56, Dunedin, New Zealand (e-mail: ian.morison{at}otago.ac.nz).
In a recent issue of the Journal, Ravenel et al. (1) claim that loss of imprinting (LOI) of the insulin-like growth factor-II (IGF2) gene defines a molecular subgroup of Wilms tumors that have a different pathologic subtype, a later age of onset, and greater IGF2 expression than those without LOI. On the basis of their findings, they propose a model for Wilms tumorigenesis. We question their conclusions and model for several reasons.
First, their conclusions rely on the pathologic classification of Wilms tumors into perilobar nephrogenic rest (PLNR)-like or intralobar nephrogenic rest (ILNR)-like tumors proposed by Beckwith et al. (2). However, Ravenel et al. (1) used only two of the four original criteria proposed by Beckwith et al.the presence or absence of PLNR or ILNRs and the presence or absence of heterologous elementsto classify the Wilms tumors in their study. Although the use of only two criteria may simplify the classification of Wilms tumors according to whether they are ILNR-like or PLNR-like, Ravenel et al. found, as we have (see below), that a substantial proportion of the tumors in their study were unclassifiable.
Second, Ravenel et al. found strong associations between chromosome 11p loss of heterozygosity (LOH) and ILNR-like tumors and between IGF2 LOI and PLNR-like tumors. We previously reported a detailed study of 24 Wilms tumors and did not find similarly strong associations (3). In our study, all five tumors associated with PLNRs displayed LOI, whereas heterologous elements (always rhabdomyoblastic) were found in both LOI tumors (5 of 9) and non-LOI tumors (6 of 15). In addition, our data illustrate the difficulties in classifying Wilms tumors, because only three of our nine tumors that displayed LOI would have been classified as PLNR-like (presence of PLNR, absence of heterologous elements) according to the criteria used by Ravenel et al.
Third, the model of Ravenel et al. (1) proposes that increased IGF2 expression is restricted to tumors with LOI. However, LOH of chromosome 11p15, which is associated with reduplication of the paternal chromosome (4,5), also doubles the number of active copies of IGF2. Furthermore, in Wilms tumors, the major determinants of IGF2 expression are independent of heterozygosity or imprinting status (5). In addition, because Ravenel et al. did not distinguish between the different types of LOH (e.g., those that affect chromosome 11p15 only, those that affect chromosome 11p13 only, and those that affect both regions), the model they propose cannot separate the effects of increased expression of IGF2 from loss of expression of the tumor suppressor gene WT1, which resides at 11p13.
Fourth, we found no difference in age at diagnosis for patients with Wilms tumors that did and did not display LOIthe median age of nine children with LOI tumors was 30 months and the median age of 15 children with non-LOI tumors was 41 months (Becroft DM, Reeve AE, Morison IM: unpublished data).
The model proposed by Ravenel et al. may oversimplify the complex interplay of multiple genetic events that are associated with Wilms tumorigenesis, because it is based on findings from a selected group of Wilms tumors. More work is needed to derive models that address such complexity.
References
1 Ravenel JD, Broman KW, Perlman EJ, Niemitz EL, Jayawardena TM, Bell DW, et al. Loss of imprinting of insulin-like growth factor-II (IGF2) gene in distinguishing specific biologic subtypes of Wilms tumor. J Natl Cancer Inst 2001;93:1698703.
2 Beckwith JB, Kiviat NB, Bonadio JF. Nephrogenic rests, nephroblastomatosis, and the pathogenesis of Wilms tumor. Pediatr Pathol 1990;10:136.[Medline]
3 Becroft DM, Okamoto K, Morison IM, Reeve AE. Perilobar nephrogenic rests are associated with epigenetic changes at the IGF2/H19 locus in developing kidney [abstract]. Pediatr Dev Pathol 1998;1:251.
4 Fearon ER, Vogelstein B, Feinberg AP. Somatic deletion and duplication of genes on chromosome 11 in Wilms tumours. Nature 1984;309:1768.[Medline]
5 Wang WH, Duan JX, Vu TH, Hoffman AR. Increased expression of the insulin-like growth factor-II gene in Wilms tumor is not dependent on loss of genomic imprinting or loss of heterozygosity. J Biol Chem 1996;271:2786370.
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