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“X” marks the spot for new Wilms’ tumor gene

Wilms tumor with a WTX deletion

Array CGH results for a Wilms tumor with a WTX deletion. All probes on the X-chromosome are shown. For most probes the tumor signal is the same as the normal signal (log ratio of 0). In contrast, the signal from tumor DNA is significantly decreased for probes that map to the WTX gene (arrowhead).

When investigators went hunting for a gene implicated in Wilms’ tumor – the most common pediatric kidney cancer – they found it in an unlikely spot. The new gene, called WTX, is the first tumor suppressor gene discovered on the X chromosome and, unlike other tumor suppressors, requires only a single damaging mutation or deletion to inactivate it.

Wilms’ tumor has long been a research focus of Daniel Haber, PhD, deputy associate director of development for the DF/HCC Executive Council and director of the MGH Cancer Center, who was one of the scientists that identified the first Wilms’ tumor gene, WT1, in 1990. Since mutations in WT1 account for only about five percent of cases, however, Haber and colleagues sought to find other genes that might play a role in the cancer – the fourth most common childhood malignancy – which occurs in about one in 10,000 children. Although most cases of Wilms’ tumor are curable with surgery and chemotherapy, treatments fail in up to 20 percent of patients.

Investigators used array comparative genomic hybridization (aCGH), a high-resolution screen for DNA copy number aberrations, to look for amplifications or deletions in the DNA of Wilms’ tumors from 82 patients. aCGH measures binding of DNA to oligonucleotides – short pieces of DNA about 30 to 60 base pairs in length that encompass the entire genome – to detect differences between tumor DNA and normal DNA, explains Miguel Rivera, MD, an instructor in pathology at MGH who is the first author of the study.

Investigators found that 30 percent of the tumors had either whole deletions of WTX or inactivating point mutations of this gene on the X chromosome. Because the gene is located on the sex-determining chromosome, explains Haber, “it only takes a single genetic event to inactivate WTX in either males or females.” (Females have two X chromosomes, but only one is active.) “That’s in contrast to other tumor suppressor genes, which can be inactivated only by independent mutations affecting both copies of the gene.”

If a single hit can shut down WTX, why is it that Wilm’s tumor is not more common? “It’s not clear,” says Rivera, “but we think it’s because of the short window of development in which these tumors can arise. Kidney stem cells, the presumed origin of Wilms’ tumor, are only present during early development and are rarely seen past age one.”

As part of a project within the Kidney Cancer SPORE, investigators are now studying the normal function of WTX in animal models and its prognostic significance using tumor specimens that are linked to clinical outcome data. A better understanding of the genetics of Wilms’ tumor, says Rivera, may one day help scientists design therapies for those cases that are refractory to standard treatment.

This research may yield broader applications as well, says Haber. “Following up on these findings should help us better understand Wilms’ tumor and may lead to a new appreciation of the X chromosome’s role in other forms of cancer.”

Lonnie Christiansen