Multiple genetic loci within 11p15 defined by Beckwith-Wiedemann syndrome rearrangement breakpoints and subchromosomal transferable fragments

Jan M.N. Hoovers, Linda M. Kalikin, Laura A. Johnson, Marielle Alders, Bert Redeker, David J. Law, Jet Bliek, Marja Steenman, Mary Benedict, Joop Wiegant, Christoph Lengauer, Patti Taillon-Miller, David Schlessinger, Michael C. Edwards, Stephen J. Elledge, Al Ivens, Andries Westerveld, Peter Little, Marcel Mannens, Andrew P. Feinberg

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108 Scopus citations


Beckwith-Wiedemann syndrome (BWS) involves fetal overgrowth and predisposition to a wide variety of embryonal tumors of childhood. We have previously found that BWS is genetically linked to 11p15 and that this same band shows loss of heterozygosity in the types of tumors to which children with BWS are susceptible. However, 11p15 contains >20 megabases, and therefore, the BWS and tumor suppressor genes could be distinct. To determine the precise physical relationship between these loci, we isolated yeast artificial chromosomes, and cosmid libraries from them, within the region of loss of heterozygosity in embryonal tumors. Five germ-line balanced chromosomal rearrangement breakpoint sites from BWS patients, as well as a balanced chromosomal translocation breakpoint from a rhabdoid tumor, were isolated within a 295- to 320-kb cluster defined by a complete cosmid contig crossing these breakpoints. This breakpoint cluster terminated approximately 100 kb centromeric to the imprinted gene IGF2 and 100 kb telomeric to p57(KIP2), an inhibitor of cyclin-dependent kinases, and was located within subchromosomal transferable fragments that suppressed the growth of embryonal tumor cells in genetic complementation experiments. We have identified 11 transcribed sequences in this BWS/tumor suppressor coincident region, one of which corresponded to p57(KIP2). However, three additional BWS breakpoints were >4 megabases centromeric to the other five breakpoints and were excluded from the tumor suppressor region defined by subchromosomal transferable fragments. Thus, multiple genetic loci define BWS and tumor suppression on 11p15.

Original languageEnglish (US)
Pages (from-to)12456-12460
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number26
StatePublished - Dec 19 1995

ASJC Scopus subject areas

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