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Inactivation of H19, an Imprinted and Putative Tumor Repressor Gene, Is a Preneoplastic Event during Wilms' Tumorigenesis¹

Department of Animal Development and Genetics, Uppsala University, S-752 36 Uppsala [H. C., F. H., L. H., S. P-O., R. O.]; Department of Paediatrics, University Hospital, S-751 85 Uppsala [F. H., S. P-O.]; Department of Clinical Genetics, Karolinska Hospital, S-17176 Stockholm [A. N.]; and Department of Pathology, Paediatric Unit. Karolinska Hospital, S-17176 Stockholm [B. S.], Sweden

Genetic evidence shows that the parent of origin-dependent expression patterns of the Igf2 and H19 genes is coordinated in mouse, such that H19 controls the activity of Igf2 in cis. Equally compelling evidence for a similar situation in humans is absent, although the frequently observed activation of the maternal IGF2 allele (i.e., loss of imprinting) in Wilms' tumors has been attributed to the silencing of the maternal H19 locus. We show here that loss of H19 activity is generally a preneoplastic event, which may be linked with an overgrowth lesion that has been proposed to be permissive for tumor formation. Although our results document one instance in which a postneoplastic loss of H19 activity correlates with loss of IGF2 imprinting at the cellular level, it appears that inactivation of H19 is more generally independent of loss of imprinting of IGF2, at least in our specimens. Our results imply that inactivation of H19 correlates with blastema overgrowth and can be independent of a regulatory role with respect to IGF2 imprinting status in cis.

¹ This work was supported by the Swedish Paediatric Cancer Foundation, the Swedish Cancer Research Foundation, the Natural Science Research Council, the Wenner-Gren Foundation, and the von Hofsten Foundation.

² To whom requests for reprints should be addressed, at Department of Animal Development and Genetics, Uppsala University, Norbyvägen 18A, S-752 36 Uppsala.

Received 7/10/97. Accepted 8/29/97.

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