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Mosaic Allelic Insulin-like Growth Factor 2 Expression Patterns Reveal a Link between Wilms’ Tumorigenesis and Epigenetic Heterogeneity¹

Department of Animal Development and Genetics, Uppsala University, S-752 36 Uppsala, Sweden [R. O., H. C., L. H., S. P., H. M., F. H.]; School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205 [H. C., L. H., S. J., A. P. F.]; Department of Pediatrics, University Hospital, S-751 85 Uppsala, Sweden [S. P., F. H.]; Department of Genetics and Pathology, Uppsala University, S-751 23 Uppsala [F. H.]

Numerous observations link the loss of imprinting of insulin-like growth factor 2 (IGF2) and an overdosage of this growth factor gene with cancer, in general, and with Wilms’ tumorigenesis, in particular. It is not known, however, if loss of imprinting correlates with specific stages of neoplasia or if allelic expression patterns vary within the tumor. By applying an allele-specific in situ hybridization technique to formalin-fixed thin sections, we show that the parental IGF2 alleles can be differentially expressed, not only in Wilms’ tumors, but also in nephrogenic rests (which represent premalignant lesions) of Wilms’ tumor patients. Moreover, a subpopulation of mesenchymal cells, which surrounds tumor nodules, expresses IGF2 biallelically irrespective of the imprinted state of IGF2 within the tumor. These data show that Wilms’ tumorigenesis involves epigenetic heterogeneity as visualized by variable allelic IGF2 expression patterns.

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