WTX inactivation is a frequent, but late event in Wilms tumors without apparent clinical impact.

Wilms tumor (WT) is one of the most common solid tumors in childhood. Mutations in WT1 and CTNNB1 are well established as causal alterations in about 10-15% of cases. Recently, WTX (WT gene on the X-chromosome), a gene implicated in WNT signaling, has been identified as a third WT gene. We determined the mutation status of WTX, CTNNB1, and WT1 in a large set of 429 tumors. Genomic WTX alterations were identified in 17% of WTs, equally distributed between males and females. Analysis of 104 WT samples for WTX point mutations revealed a rate of only 2%. An additional 11.5% of tumor samples lacked expression of WTX mRNA. These WTX alterations can occur in parallel to WT1 or CTNNB1 mutations. However, we could not find a significant correlation between WTX deletion status or expression level and clinical parameters suggesting that WTX mutations apparently have little direct impact on tumor behavior and presentation. Incomplete deletions of WTX in several cases suggested heterogeneity in tumors. In a small number of cases, we could analyze separate tumor fragments or microdissected regions with different histology of tumors with heterozygous point mutations. Despite complete allele losses at other sites in the genome, we detected varying degrees of WTX mutation. This suggests that WTX alteration is not an essential and early mutation needed to drive tumorigenesis, but rather a later event that may affect only a fraction of cells with unclear clinical relevance.