Paternally Inherited Submicroscopic Duplication at 11p15.5 Implicates Insulin-like Growth Factor II in Overgrowth and Wilms' Tumorigenesis

Abstract

Loss of imprinting at insulin-like growth factor II (IGFII), in association with H19 silencing, has been described previously in a subgroup of Beckwith-Wiedemann syndrome (BWS) patients who have an elevated risk for Wilms' tumor. An equivalent somatic mutation occurs in sporadic Wilms' tumor. We describe a family with overgrowth in three generations and Wilms' tumor in two generations, with paternal inheritance of a cis-duplication at 11p15.5 spanning the BWS IC1 region and including H19, IGFII, INS, and TH. The duplicated region was below the limit of detection by high-resolution karyotyping and fluorescence in situ hybridization, has a predicted minimum size of 400 kb, and was confirmed by genotyping and gene-dosage analysis on a CytoChip comparative genomic hybridization bacterial artificial chromosome array. IGFII is the only known paternally expressed oncogene mapping within the duplicated region and our findings directly implicate IGFII in Wilms' tumorigenesis and add to the mutation spectrum that increases the effective dose of IGFII. Furthermore, this study raises the possibility that sporadic cases of overgrowth and Wilms' tumor, presenting with apparent gain of methylation at IC1, may be explained by submicroscopic paternal duplications. This finding has important implications for determining the transmission risk in these disorders. [Cancer Res 2007;67(5):2360-5]

New insights into the pathogenesis of beckwith-wiedemann and silver-russell syndromes: Contribution of small copy number variations to 11p15 imprinting defects

“…The S72P cis-duplication involves only part of the IGF2/H19 domain (the imprinting control region and the H19 gene) and results in a SRS phenotype only if maternally inherited when there is no phenotype upon paternal transmission. Both the parental transmission pattern and the phenotype are different from previously reported ICR1 duplications [Algar et al, 2007;Bliek et al, 2009b;Russo et al, 2006]. Cis-duplications (0.3-1.8 Mb in size) involving the whole IGF2/H19 domain have been previously reported in two familial [Algar et al, 2007;Bliek et al, 2009b] and one sporadic [Russo et al, 2006] BWS cases.…”

“…They resulted in BWS only if the paternal chromosome was involved. The main difference between the S72P duplication and other duplications of the IGF2/H19 domain ( [Algar et al, 2007;Bliek et al, 2009b;Russo et al, 2006] and the H47P case) is that the S72P duplication involves ICR1 and the H19 gene but does not involve the IGF2 gene. Although two CNVs [Bliek et al, 2009b] (Supp.…”

Clinical significance of copy number variations in the 11p15.5 imprinting control regions: new cases and review of the literature

“…13 14 In contrast, a BWS phenotype can be observed in case the duplication of maternal material is restricted to the KCNQ1OT1 DMR or the putative CDKN1C enhancer region 5 7. Interestingly, the deletion of the maternal copy of both the KCNQ1OT1 DMR and the putative CDKN1C enhancer results in BWS, whereas the phenotype is normal if the paternal allele is deleted 6 15…”

Candidate genes and potential targets for therapeutics in Wilms’ tumour

“…In this study, it was found that the precipitating factor in the development of WT was the increase in effective IGF2 dosage in the absence of alteration of H19. However, it is still thought that a second hit is required in addition to the increase in IGF2 gene product as a subject was identified in this study who remained free of WT despite having this paternally inherited cis-duplication of IGF2 [122].…”