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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 withimprinting 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.

human molecular genetics

Tumor development in the Beckwith–Wiedemann syndrome is associated with a variety of constitutional molecular 11p15 alterations including imprinting defects of  KCNQ1OT1