The WT1 gene essential for the embryonic kidney development is mutated in 15-25% of Wilms tumors (WTs). To clarify whether genetic subtypes of WT1 abnormalities are correlated with IGF2 or CTNNB1 alterations or clinicopathological characteristics, we performed comprehensive WT1, IGF2, and CTNNB1 analyses of 36 WTs with WT1 abnormalities using single nucleotide polymorphism arrays, and methylation analysis of the IGF2-H19 differentially methylated region. The tumors were classified into three subtypes based on WT1 abnormalities: 13 with WT1 deletion, 12 with WT1 mutation, and 11 with both deletion and mutation. IGF2 alterations were found in 50% (18/36), paternal uniparental disomy (UPD) of 11p13-11p15 in 13 tumors, UPD limited to 11p15 in 3, and loss of IGF2 imprinting in 2. Quantitative RT-PCR analysis showed that tumors with IGF2 alteration had higher levels of IGF2 mRNA than tumors without IGF2 alteration (P = 0.02). WT1 mRNA levels were very low in six of eight WTs with WT1 deletion, whereas four of eight WTs with WT1 mutation or both deletion and mutation showed higher levels of WT1 mRNA than fetal kidneys. WTs with WT1 mutations occurred in younger patients (P < 0.01), and WTs with mutations or both deletion and mutation (12/23) were more frequent in syndromic patients than WTs (1/13) with the deletion (P = 0.02). WTs with WT1 mutations or both deletion and mutation had the triphasic histological-type (15/23; P = 0.03) and CTNNB1 mutation (17/23; P = 0.03) more frequently than WTs with the deletion (2/13 and 4/13). Thus, three WT1 subtypes were correlated with certain genetic and clinicopathological characteristics.
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