Splicing Variants of Carbonic Anhydrase IX in Bladder Cancer and Urine Sediments.
Gabriella Nesi, Francesca Malentacchi, Serena Vinci, Donata Villari, Cesare Selli, Claudio Orlando. University of Florence, Italy; University of Pisa, Italy
Background: In human cancers, carbonic anhydrase IX (CAIX) influences cell proliferation and tumor progression, maintaining intracellular and extracellular pH under hypoxic conditions. An alternative CAIX isoform, lacking exons 8-9 (AS) and independent from the levels of hypoxia, was recently demonstrated in cancer cells. AS-CAIX competes with the full-length (FL) isoform in the regulation of extracellular pH, in a mainly mild hypoxic status. In the present study we evaluated mRNA expression of the two CAIX isoforms and their clinical relevance in bladder carcinomas and urine sediments.
Design: We measured mRNA expression of FL- and AS-CAIX isoforms in tumor tissues and benign mucosa from 45 patients with urothelial carcinoma of the urinary bladder. The expression of the two isoforms was also measured in the urine sediment of 81 bladder cancer patients and 93 control subjects.
Results: Expression of FL-CAIX mRNA was lower than AS-CAIX in benign mucosa (p=0.006) whereas in paired bladder cancers FL-CAIX mRNA was higher (p=0.007). Consequently, the percentage of FL-CAIX in bladder cancers (median: 62.6%) was significantly higher than in benign mucosa (15.0%) (p<0.0001). In the urinary sediments of bladder cancer patients, FL-CAIX mRNA was significantly higher in comparison to normal controls (p=0.003). FL-CAIX percentage appeared dramatically higher in urine sediments of bladder cancer patients (64.5%) in comparison to controls (7.5%) (p<0.0001). In addition FL-CAIX% was significantly different in sediments from pTa-pT1 and ≥pT2 patients (51.5% and 91.7%, respectively) (p=0.016). Stratification according tumor grade indicated that FL-CAIX% was significantly reduced in low-grade urothelial papillary carcinomas (33.3%) in comparison to high-grade (88.6%) (p=0.005) The clinical sensitivity for FL-CAIX% in urine sediments was 0.93, with a 0.76 specificity. Using the same cut-off, positive predictive value was 0.78, whereas negative predictive value was 0.93.
Conclusions: Our results seem to indicate that, in bladder cancers and related urine sediments, FL-CAIX is the prevalent and most accurate, clinically relevant variant surrogate of hypoxic stress.
Category: Genitourinary (including renal tumors)
Tuesday, March 1, 2011 9:30 AM
Poster Session III # 181, Tuesday Morning