Variation in Gene May Increase Risk of Bladder Cancer

September 2009

Prostate Stem Cell Antigen (PSCA) Is a Factor

Researchers have pinpointed a specific gene variation that causes increased risk of urinary bladder cancer.

In the future, scientists hope the results of this large, multicenter international study may help determine who is at high risk for this deadly cancer, which may lead to improved screening and targeted chemopreventive interventions.

Researchers from M. D. Anderson published this landmark study in the Aug. 2 advance online edition of Nature Genetics.

Significance of research

“With this research, we found a novel specific gene and a functional variation that are independent of the previous suspects,” says Xifeng Wu, M.D., Ph.D., professor in M. D. Anderson’s Department of Epidemiology, the lead and corresponding author.

“We found a ‘why’ to many of the questions about genetic causes of bladder cancer,” she says.

Bladder cancer is the fourth most common cancer in men in the United States. In this country, more than 68,800 new cases will be diagnosed and approximately 14,400 people will die from the disease this year.

Cigarette smoking and occupational exposure to certain chemicals are known risk factors, but almost one-third of people who get the disease have an inherited genetic susceptibility. People with first-degree relatives with bladder cancer have a 50% to 100% higher risk.

Background

The exact genetic explanation for bladder cancer remains to be found, but this study may help solve some of the puzzles, Wu says.

Prostate stem cell antigen (PSCA) is over-expressed in prostate cancer, and the level of PSCA increases with grade and stage in prostate cancer tumors. However, the cellular function of PSCA is not clear.

While PSCA’s involvement in bladder cancer had been suggested previously, this is the first time it has been linked definitively.

Research methods

The first step of this study was a genome-wide study of:

969 people with bladder cancer
954 healthy people

To validate their findings, researchers evaluated patients from three additional U.S. and nine European groups, for a total of:

6,667 people with bladder cancer
39,590 healthy people

Primary results

A variant in the PSCA gene (rs2294008) was associated consistently with bladder cancer. People with the variant had a 30% to 40% higher risk for bladder cancer.

In the PSCA gene region, rs2294008 was the only common missense (the amino acid sequence of a gene product is changed) genetic variation.

The variant significantly reduced the promoter (a portion of a gene that activates it and drives its expression) activity of the PSCA gene in cell culture systems. This suggests rs2294008 may cause increased bladder cancer risk.

Low levels of PSCA were found in the bladders of healthy people, but it was over-produced in the majority of patients with bladder cancer.

Previous reports suggest that measurement of PSCA in urine may be a simple and accurate marker to help diagnose bladder cancer.

What’s next?

The group plans to fully analyze data jointly with other participating centers, possibly uncovering additional genes for bladder cancer.

Wu said she hopes the group’s findings will help targeted bladder cancer prevention efforts.

“When we’ve identified all the genes that are linked to bladder cancer, we plan to develop a Web-based tool so physicians can calculate accurately and easily a patient’s risk of getting the disease. Early identification of risk may help save lives with chemoprevention or early treatment.”

Adapted by Dawn Dorsey from an M. D. Anderson news release.