Wilms tumour histology is determined by distinct types of precursor lesions and not epigenetic changes#π

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Current models of Wilms tumour development propose that histological features of the tumours are programmed by the underlying molecular aberrations. For example, tumours associated withWT1mutations arise from intralobar nephrogenic rests (ILNR), concur withCTNNB1mutations and have distinct histology, whereas tumours withIGF2loss of imprinting (LOI) often arise from perilobar nephrogenic rests (PLNR). Intriguingly, ILNR and PLNR are found simultaneously in Wilms tumours in children with overgrowth who have constitutionalIGF2LOI. We therefore examined whether the precursor lesions or early epigenetic changes are the primary determinant of Wilms tumour histology. We examined the histological features and gene expression profiles ofIGF2LOI tumours andWT1-mutant tumours which are associated with PLNR and/or ILNR. Two distinct types ofIGF2LOI tumours were identified: the first type had a blastemal-predominant histology associated with PLNR, while the second subtype had a myogenic histology, increased expression of mesenchymal lineage genes and an association with ILNR, similar toWT1-mutant tumours. These ILNR-associatedIGF2LOI tumours also showed signatures of activation of the WNT signalling pathway: differential expression of β-catenin targets (MMP2, RARG, DKK1) and WNT antagonist genes (DKK1, WIF1, SFRP4). Unexpectedly, the majority of these tumours hadCTNNB1mutations, which are normally only seen inWT1-mutant tumours. The absence ofWT1mutations in tumours withIGF2LOI indicated thatCTNNB1mutations occur predominantly in tumours arising from ILNR independent of the presence or absence ofWT1mutations. Thus, even though these two classes of tumours withIGF2LOI have the same underlying predisposing epigenetic error, the tumour histology and the gene expression profiles are determined by the nature of the precursor cells within the nephrogenic rests and subsequentCTNNB1mutations. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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