Association of chromosome arm 16q loss with loss of imprinting of insulin-like growth factor-II in Wilms tumor.
The most common known molecular defect in Wilms tumor (WT) of the kidney, the most frequent solid tumor of childhood, is loss of imprinting (LOI) of the insulin-like growth factor-II gene (IGF2), which involves activation of the normally silent maternal allele of the gene and hypermethylation of a differentially methylated region upstream of the H19 gene. Hypermethylation impairs binding of the insulator protein CTCF, allowing activation of IGF2 by an enhancer shared between IGF2 and H19. Loss of heterozygosity (LOH) of 16q22.1 is found in 15% of WTs, and 16q22.1 harbors CTCF, raising the possibility that reduced CTCF could lead to LOI of IGF2 in some cases. We hypothesized that there is an association between LOH of 16q and LOI of IGF2 in WT. In 40 WTs examined, LOH of 16q was found in five, one of which also showed LOH of 11p15. All of the remaining four tumors showed LOI of IGF2, compared to 13 of 32 WTs without LOH of 16q or 11p (P = 0.040). When published data not previously analyzed in this manner were included, 6 of 6 tumors with 16q LOH (and without LOH of 11p) showed LOI of IGF2, compared to 24 of 52 without LOH (P = 0.015). Thus, a genetic (16q LOH) and an epigenetic (LOI of IGF2) alteration in WT are linked, the first such association described. Finally, haploinsufficiency of CTCF may be the basis of this association, given that CTCF expression in tumors with 16q LOH was 48% that of tumors without LOH.
Mummert
Stephanie K
SK
Graduate Program in Biochemistry, Cell and Molecular Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Lobanenkov
Victor A
VA
Feinberg
Andrew P
AP
D001483:Base Sequence; D002872:Chromosome Deletion; D002885:Chromosomes, Human, Pair 16; D017931:DNA Primers; D018392:Genomic Imprinting; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D019656:Loss of Heterozygosity; D020133:Reverse Transcriptase Polymerase Chain Reaction; D009396:Wilms Tumor / Q000235:genetics*
D017931:DNA Primers; D007335:Insulin-Like Growth Factor II