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Genetic biomarker identified in bladder cancer tumors
Patients who inherited the common genetic variant rs2294008 were later found to develop bladder cancer tumors that strongly express prostate stem cell antigen, also found in many pancreatic and prostate tumors.
“Up to 75% of bladder cancer patients of European descent are estimated to carry the risk rs2294008 CT and TT genotypes,” Ludmila Prokunina-Olsson, PhD, of the NCI’s division of cancer epidemiology and genetics, and colleagues wrote. “Possibly, if used at early cancer stages, anti-[prostate stem cell antigen] immunotherapy might prevent progression to advanced muscle invasive cancer, a devastating disease that is treated by radical bladder cystectomy together with removal of parts of surrounding organs and lymph nodes to prevent metastasis.”
Ludmila Prokunina-Olsson
In a prior study, Prokunina-Olsson and colleagues identified increased prostate stem cell antigen (PSCA) mRNA expression in bladder tumors and, specifically, in the presence of the risk T allele of rs2294008.
To determine whether PSCA could provide a candidate drug target for bladder cancer, as well as prostate and pancreatic cancers, the researchers performed RNA sequencing of six normal and six tumor bladder tissues, and validation studies in 14 normal and 13 tumor bladder tissue samples heterozygous for rs2294008. In addition, the researchers quantified rs2294008 T and C alleles in DNA and cDNA samples and calculated an average tumor-to-normal ratio.
In DNA samples, the tumor to normal ratio was close to 1.0 and comparable for both alleles, suggesting no difference in DNA copy number variation between normal and tumor tissues within the PSCA gene.
“This is an important conclusion because PSCA is located in 8q24.3 region and relatively close to MYC oncogene in 8q24.21 region, which is reported to be amplified in many cancers,” Prokunina-Olsson and colleagues wrote. “Thus, our results do not support the involvement of PSCA in differential genomic amplification in bladder tumors.”
Clinical trials would be needed to validate PSCA as a therapeutic target in bladder cancer and rs2294008 as a predictive marker for treatment response, the researchers said. Additionally, more investigation is required to develop alternative drugs that target PSCA and to evaluate alternative approaches, such as intravesical administration of the anti-PSCA antibody and/or its conjugation with other bioactive molecules to enhance treatment efficiency and facilitate bladder tumor-specific drug delivery.
“We’ve been pursuing this mechanism for some time now,” Ludmila Prokunina-Olsson said in a press release. “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.”
Disclosure: The researchers report no relevant financial disclosures.