Molecular definition of the 11p15.5 region involved in Beckwith-Wiedemann syndrome and probably in predisposition to adrenocortical carcinoma

Abstract

To define more precisely, in molecular terms, the region involved in Beckwith-Wiedemann syndrome (BWS), we have studied patients with BWS and a constitutional duplication of 11p15 using eight 11p15 markers. In the first case with a de novo duplication and extra material on 11p, the region spanning pter to CALCA, excluded, was duplicated. In the second case, the rearrangement was characterized using somatic cell hybrids established with lymphocytes from the father who carried a balanced translocation t(11;18)(p15.4;p11.1). The breakpoint lay exactly in the same region. It could thus be inferred that the two sons, who were the first cases reported of BWS with dup11p15 and adrenocortical carcinoma (ADCC), carried a duplication similar to that observed in the first case. Together with evidence for specific somatic chromosomal events leading to loss of 11p15 alleles in familial cases of ADCC, it can be hypothesized that a gene involved in predisposition to ADCC maps to region 11p15.5.

Tumor-specific loss of 11p15.5 alleles in del11p13 Wilms tumor and in familial adrenocortical carcinoma.

“…According to the consensus gene order of the markers on lip (29), this region extends from pter to CALCA excluded (19). Specificity of the region involved is crucial.…”

“…We also tested the same hypothesis-i.e., a somatic mutation in 11p15 for ADCC. We based this test on clues as to the location of a gene for susceptibility to ADCC provided by the molecular definition of a constitutional duplication of 11p15.5 in a BWS patient with ADCC and by the increased frequency of ADCC in patients with BWS (7,19,20 …”

The human MyoD1 (MYF3) gene maps on the short arm of chromosome 11 but is not associated with the WAGR locus or the region for the Beckwith-Wiedemann syndrome

“…To study the moredistal region of chromosome llp in more detail, additional somatic cell hybrlds defming the smallest region of overlap of the Beckwith-Wiedemann locus were used (Henry et al 1989b • with the breakpoint in llp15.4 were analyzed with the myf3 probe. As shown in Fig.…”

“…The Beckwith-Wiedemann syndrome, a rare condition of growth abnormalities, has also been cytogenetically located on chromosome 11 p (Waziri et al 1983) and physically and genetically mapped to llp15.5 , Henry et al 1989bPing et al 1989). Individuals with Beckwith-Wiedemann syndrome carry an increased risk for the same three embryonic tumors (Sotelo-Avila and Gooch 1976).…”

Insights into the role of genetic alterations in adrenocortical tumorigenesis

“…The gene locus responsible for this syndrome was mapped to M a n u s c r i p t 5 chromosome 11p15 (Henry et al, 1989), which includes the Insulin-like Growth Factor 2 (IGF-2), H19, and cyclin-dependent kinase inhibitor C (p57/kip2). This locus is subject to parental imprinting with IGF-2 solely expressed from the paternal allele, and H19 and p57/kip2 normally expressed from the maternal allele.…”