Wilms Tumor 2
A number sign (#) is used with this entry because of evidence that Wilms tumor-2 (WT2) is caused by mutation of the H19/IGF2-imprinting control region (ICR1; 616186) on chromosome 11p15. ICR1 controls imprinted expression of H19 (103280) and IGF2 (147470).
ICR1 and a neighboring imprinted gene cluster are implicated in Beckwith-Wiedemann syndrome (BWS; 130650), of which Wilms tumor is a common feature.
For a general phenotypic description and discussion of genetic heterogeneity of Wilms tumor, see WT1 (194070).
MappingUsing a range of probes for chromosome 11, Mannens et al. (1988) demonstrated that loss of heterozygosity in Wilms tumors may involve chromosome 11p15.5 in addition to 11p13. Jeanpierre et al. (1990) found loss of maternal alleles from the 11p15 area of the maternal chromosome in Wilms tumor tissue and a constitutional deletion of 11p13 of the maternal chromosome. The authors noted that there have been other instances in which the 11p region involved in loss of heterozygosity (11p15) is different from the region involved in hereditary predisposition (11p13).
Koufos et al. (1989) studied patients with sporadic Wilms tumors, not associated with BWS, and found that a subset of the tumors had attained somatic homozygosity through mitotic recombination, with the smallest shared region of overlap being distal to the beta-globin complex at 11p15.5. The data suggested that there is a second locus, distinct from that on 11p13, that plays a role in the Wilms tumor. See also Henry et al. (1989).
Reeve et al. (1989) found loss of allelic heterozygosity at polymorphic 11p15 loci in Wilms tumor cells from 5 patients. In cells of 1 tumor, mitotic recombination had occurred distal to the gamma-globin gene on 11p15.5. Wadey et al. (1990) found that some Wilms tumors had allele loss restricted to 11p15 or to 11p13 and distal sequences.
Dowdy et al. (1991) provided in vivo functional evidence for the existence of this second genetic locus involved in suppressing the tumorigenic phenotype of Wilms tumor: they constructed a chromosome 11 that had one or the other region deleted, and this chromosome was introduced into the tumorigenic Wilms tumor cell line G401. When assayed for tumor-forming activity in nude mice, the 11p13-deleted, but not the 11p15.5-p14.1-deleted chromosome, retained its ability to suppress tumor formation.
Molecular GeneticsUsing methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) of the 11p15 growth regulatory region, Scott et al. (2008) identified constitutional abnormalities at chromosome 11p15 in 13 (3%) of 437 individuals with sporadic Wilms tumor without features of overgrowth syndromes. Six patients had paternal uniparental disomy of 11p15 and 6 had hypermethylation at the H19 differentially methylated region (DMR) (see ICR1, 616186). There were 2 familial cases. In 1 family, 2 sibs had a microdeletion of the H19 DMR (616186.0002) that was inherited from the unaffected mother; 1 sib had isolated Wilms tumor and the other had features of BWS. In a second family, a mother and 2 daughters had a microinsertion in the H19 DMR (616186.0003), inherited from the unaffected grandmother. No abnormalities were detected in 220 controls. Analysis of tumor tissue showed that the level of H19 DMR hypermethylation was greater in tumor compared to lymphocytes, suggesting that the tumors developed by clonal expansion of cells harboring the 11p15 defect. There was no evidence of additional tumor-specific 11p15 abnormalities affecting the wildtype allele.