Bladder cancer genetic variant identified

Patients who have inherited a specific common genetic variant develop bladder cancer tumors that strongly express a protein known as prostate stem cell antigen (PSCA), which is also expressed in many prostate and pancreatic tumors, say researchers from the National Cancer Institute, Bethesda, MD.

A therapy targeting the PSCA protein on the tumor cell surface is under evaluation in clinical trials for prostate and pancreatic cancer. The authors hope that this therapy will be tested in bladder cancer patients with the genetic variant, which could help to reduce potentially harmful side effects, lower costs, and improve treatment efficacy.

In a previous study, the authors identified a variant located in the PSCA gene on chromosome 8 as associated with bladder cancer susceptibility. The gene determines whether the corresponding protein is expressed in bladder tumor tissue.

In the latest report, published in the Journal of the National Cancer Institute (2013; 105:69-73), the authors found that the "T" nucleotide that comprises a gene variant called rs2294008 is a strong predictor of PSCA protein expression. The variant results in increased delivery of the protein to the cell surface, where it is involved in signaling and promotes tumor growth.

"We've been pursuing this mechanism for some time now. It started with our early results from the initial genome-wide association study that revealed a marker in the PSCA gene related to bladder cancer risk. This latest work reveals how a specific letter change in DNA influences protein expression at the cell surface. The big payoff is that a simple genetic test can determine which patients could benefit from anti-PSCA therapy," said senior author Ludmila Prokunina-Olsson, PhD.

The authors note that additional work is needed to develop alternative drugs targeting PSCA, and to evaluate drug delivery methods, such as systemic delivery for advanced muscle-invasive tumors and local, inter-bladder delivery in the case of nonmuscle-invasive tumors. Anti-PSCA therapy is likely to be effective only against tumors that express PSCA. A genetic test for the "T" nucleotide of this genetic variant can identify bladder cancer patients who could benefit from this treatment.