Gene May Help Trigger Children's Kidney Cancer

Discovery of Wilms' tumor mutation has implications for cancer research generally, experts add

THURSDAY, Jan. 4, 2007 (HealthDay News) -- Scientists have discovered that mutated copies of a particular gene are present in about 30 percent of children with Wilms' tumor, the most common type of pediatric kidney cancer.

The finding may one day help physicians decide which patients need more therapy, or less.

"There's always an interest in terms of clinical markers -- how can you predict the 20 percent who are not going to be cured, and those who don't need chemotherapy or more intensive treatment," said senior study author Dr. Daniel A. Haber, director of the Cancer Center at Massachusetts General Hospital in Boston. "We're hoping our gene has some relationship to these issues."

"I hope it's just another key to unlock the secrets to this tumor so that treatment and prognosis continue to improve," added Dr. Monford Custer III, an associate professor of surgery with the Texas A&M Health Science Center College of Medicine. "I could foresee a future where they might utilize this to help understand or predict the tumor's biological behavior, which would be just another resource to guide treatment protocols."

The discovery also marks the first time a tumor-suppressor gene has been found on the sex-determining X chromosome, meaning that only one mutated copy of the gene, not two, would be necessary for cancer to develop. Males carry only one copy of the X chromosome, while females carry two.

"People have speculated about whether there could be tumor-suppressor genes on the X chromosomes and there have been some little hints," said Haber. "This is the first time to show that a gene inactivating a single copy inactivates the entire gene."

The finding may trigger a rush to try to find other cancer-related genes on that chromosome, he added.

"For this reason, nobody has looked at the X chromosome very carefully," Haber said. "This would be a good reason to start looking at the X chromosome."

About one of 10,000 children develop Wilms' tumor, also known as nephroblastoma. Unlike adult kidney cancer, pediatric kidney cancer is relatively easy to treat. About 80 percent of cases are curable with surgery and chemotherapy, Haber said.

"This is a real success story in oncology," Custer said. "Wilms' was one of the first tumors ever treated with multi-modal therapy, meaning surgery, radiation and chemotherapy." The survival rate has jumped from a dismal 60 percent in the 1960s to as high as 95 percent for some forms of the tumor today, Custer noted.

In 1990, scientists discovered that mutations in a gene called WT1 cause about 5 percent of cases of Wilms' tumor.

But that's a relatively small percentage and, said Haber, and "we're always interested in looking for other genes."

Enter the new study, which will appear in the Jan. 4 online issue of Science.

Haber and his colleagues conducted genome screening and sequencing tests on tumor samples from 82 patients. They discovered that about 30 percent of Wilms' tumor cases have mutations or deletions in the WTX gene.

Interestingly, the WTX gene is located on the X chromosome. Females have two X chromosomes while males have only one. In females, however, one X chromosome is inactivated during normal development.

Researchers have believed that, in order for cancer to develop, both copies of a gene need to be inactivated, usually through two separate events or "hits." But humans carry only one functional allele (copy) of all genes on the X chromosome, so the WTX tumor suppressor gene apparently is inactivated with only one "hit," Haber said.

In tumor samples from female patients with Wilms' tumor, mutated copies of the WTX gene were found only on the active copy of the X chromosome.

Other known tumor-suppression genes can only be incapacitated by independent mutations in both copies of the gene.

"This is the first example of a cancer gene where one gene is inactivated instead of two," Haber said.

The discovery has created a new puzzle for researchers. "The cancer should be astronomically more common if it was just one hit," Haber noted. "We speculated that the cells that give rise to Wilms' tumor are kidney stem cells, so they differentiate over time." These stem cells are involved in normal kidney development.

The next step is to see how the discovery may help children with Wilms' tumor.

"We would like to access tumor samples and ask whether losing this gene is a good or bad prognostic marker," Haber said. "If it goes either way, it would have an impact on treatment because 30 percent is a big number. But it's also possible it could be neither."

More information

There's more on Wilms' tumor at the Association of Cancer Online Resources.

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