Human Molecular Genetics, 2001, Vol. 10, No. 26 2989-3000
© 2001 Oxford University Press
Tumor development in the Beckwith–Wiedemann syndrome is associated with a variety of constitutional molecular 11p15 alterations including imprinting defects of KCNQ1OT1
1Division of Clinical and Metabolic Genetics and the Department of Paediatrics and 2Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada, 3Department of Molecular and Medical Genetics and 4Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada, 5Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, Ontario, Canada, 6Ontario Cancer Institute, Toronto, Ontario, Canada, 7Department of Laboratory Medicine and Pathobiology and 8Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
Dysregulation of imprinted genes on human chromosome 11p15 has been implicated in Beckwith–Wiedemann syndrome (BWS), an overgrowth syndrome associated with congenital malformations and tumor predisposition. The molecular basis of BWS is complex and heterogeneous. The syndrome is associated with alterations in two distinct imprinting domains on 11p15: a telomeric domain containing the H19 and IGF2 genes and a centromeric domain including the KCNQ1OT1 and CDKNIC genes. It has been postulated that disorders of imprinting in the telomeric domain are associated with overgrowth and cancer predisposition, whereas those in the centromeric domain involve malformations but not tumor development. In this study of 125 BWS cases, we confirm the association of tumors with constitutional defects in the 11p15 telomeric domain; six of 21 BWS cases with uniparental disomy (UPD) of 11p15 developed tumors and one of three of the rare BWS subtype with hypermethylation of the H19 gene developed tumors. Most importantly, we find that five of 32 individuals with BWS and imprinting defects in the centromeric domain developed embryonal tumors. Furthermore, the type of tumors observed in BWS cases with telomeric defects are different from those seen in BWS cases with defects limited to the centromeric domain. Whereas Wilms’ tumor was the most frequent tumor seen in BWS cases with UPD for 11p15 or H19 hypermethylation, none of the embryonal tumors with imprinting defects at KCNQ1OT1 was a Wilms’ tumor. This suggests that distinct tumor predisposition profiles result from dysregulation of the telomeric domain versus the centromeric domain and that these imprinting defects activate distinct genetic pathways for embryonal tumorigenesis.
+ To whom correspondence should be addressed at: Division of Clinical and Metabolic Genetics, Hospital for Sick Children, 555 University Avenue,Toronto, Ontario M5G 1X8, Canada. Tel: +1 416 813 6386; Fax: +1 416 813 5345; Email: rweksb@sickkids.on.ca
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