One Strike Out Eliminates Probable Tumor Suppressor

A new study in Science by Rivera et al. implicates the WTX gene, located on the X-chromosome, in contributing to the pediatric renal cancer Wilms tumor. Their findings challenge the widely held notion that tumor suppressor inactivation, and cancer initiation, requires bi-allelic tumor suppressor gene loss. In about one third of both male and female Wilms tumor samples analyzed, WTX was inactivated by a single mutational event, in contrast to the classical ‘two-hit’ (bi-allelic loss) model.

Previous analysis of Wilms tumor cases pinpointed a genetic culprit in the chromosome 11 gene WT1. However, loss of this zinc-finger transcription factor critical for kidney development accounted for only 5-10% of sporadic Wilms tumor cases. Therefore, Rivera et al. sought unrecognized genetic anomalies and noted a suspicious clustering of deletions around Xq11.1, which they narrowed down to a single locus designated WTX (“Wilms Tumor gene on the X chromosome”).

Surprisingly, inactivation of a single copy of WTX was strongly associated with Wilms tumor in both males and females alike. While males have only one WTX gene on their single X chromosome, in Wilms tumors of heterozygous females the mutant copy was always on the active chromosome and the wild type form was suppressed by X-inactivation. As might be predicted, WT1 and WTX RNA were expressed in largely overlapping domains during kidney development, including in the precursor cells from which Wilms tumor apparently originates. In initial functional tests, WTX exhibited tumor-suppressing properties but confirmation of the protein’s activity during tumor formation as well as normal development requires further studies.

This seminal report exemplifies the critical role of X-chromosome genetics in cancer development. The strong association of WTX inactivation with Wilms tumor solidifies the notion that one strike can be enough to trigger a deadly cancer.

Author contact:
Daniel A. Haber
haber@helix.mgh.harvard.edu

Message posted by: Robin Kimmel