MGH Cancer Center researchers find new gene associated with Wilms tumor

Researchers at the Massachusetts General Hospital (MGH) Cancer Center have discovered a novel gene mutation associated with Wilms tumor, the most common pediatric kidney cancer. The newly identified gene is mutated in about 30 percent of cases of Wilms tumor and is located on the sex-determining X chromosome, which means that a single altered copy would be sufficient for tumor formation. The new gene does not appear linked to inherited forms of the disease.

“This is the first X chromosome gene directly implicated as a tumor suppressor,” says Daniel A. Haber, MD, PhD, director of the MGH Cancer Center and senior author of the report, which will appear in the journal Science and is receiving early online release on the Science Express website at http://www.sciencexpress.org. “It has the potential of someday being a useful prognostic marker for Wilms tumor patients, and learning about its normal function could tell us more about both normal kidney development and tumorigenesis.”

Also called nephroblastoma, Wilms tumor develops in one out of 10,000 children and is usually treated successfully with surgery and chemotherapy. Mutations in a gene called WT1, first identified in 1990, cause about 5 percent of cases, and a few other genes are associated with rare syndromes that can include Wilms tumor. Those with a family history of the disease have an increased risk of developing the cancer in both kidneys.

Since so few cases of Wilms tumor could be attributed to the identified mutations, the MGH Cancer Center researchers analyzed tumor samples from 82 patients to search for additional genetic abnormalities. Genome screening and sequencing tests showed that nearly 30 percent of the samples had either deletions or mutations in the same area of the X chromosome, indicating a new cancer gene that the researchers have named WTX. In samples from female patients, mutated copies of WTX were found only on the active copy of the X chromosome.

“Males have only one X chromosome, so for them a single mutation can silence the gene and cause a tumor,” Haber explains. “Females have two X chromosomes, but one is inactivated during normal development. We showed that mutations specifically occur on the active X in female Wilms patients, so it takes a single genetic event to inactivate WTX in either males or females. That's in contrast to other tumor suppressor genes, which only can be inactivated by independent mutations affecting both copies of the gene.”

The researchers also found that WTX is expressed in cells involved in embryonic kidney development, suggesting that it normally plays a key role in the organ's formation. They are now investigating the gene's normal function and studying its disruption in an animal model.

“The biology that links pediatric cancers to normal organ development is fascinating,” says Haber. “Adult kidney cancers arise slowly from the organ's tubules and are highly resistant to current chemotherapy drugs, but pediatric kidney tumors arise in the early stem cells of the kidney's filtering apparatus and are highly responsive to chemotherapy. Following up on these findings should help us better understand this tumor and may lead to a new appreciation of the X chromosome's role in other forms of cancer.” Haber is the Laurel Schwartz Professor of Oncology at Harvard Medical School.