A Molecular Signature in Superficial Bladder Carcinoma Predicts Clinical Outcome

Purpose: Cancer of the urinary bladder is a common malignant disease in the western countries. The majority of patients presents with superficial tumors with a high recurrence frequency, a minor fraction of these patients experience disease progression to a muscle invasive stage. No clinical useful molecular markers exist to identify patients showing later disease progression. The purpose of this study was to identify markers of disease progression using full-genome expression analysis. Experimental Design: We did a full-genome expression analysis (59,619 genes and expressed sequence tags) of superficial bladder tumors from 29 bladder cancer patients (13 without later disease progression and 16 with later disease progression) using high-density oligonucleotide microarrays. We used supervised learning for identification of the optimal genes for predicting disease progression. The identified genes were validated on an independent test set (74 superficial tumor samples) using in house-fabricated 60-mer oligonucleotide microarrays. Results: We identified a 45-gene signature of disease progression. By monitoring this progression signature in an independent test set, we found a significant correlation between our classifications and the clinical outcome (P 0.03). The genes identified as differentially expressed were involved in regulating apoptosis, cell differentiation, and cell cycle and hence may represent potential therapeutic targets. Conclusions: Our results indicate that it may be possible to identify patients with a high risk of disease progression at an early stage using a molecular signature present already in the superficial tumors. In this way, better treatment and follow-up regimens could be assigned to patients suffering from superficial bladder cancer. Editorial Comment: It is a shame that truly outstanding science may have a potentially significant confounding clinical factor that is unaccounted for. Is a T1 cancer that progresses to T2 the result of a noninvasive (high grade Ta or Tis) cancer that then becomes invasive, a T1 cancer that was incompletely resected and continues to grow into the muscle, or a T2 cancer that was under staged as a T1 and in which “progression” was already present? We know that 10% to 40% of T1 bladder cancers are incompletely resected at initial transurethral resection, that many more may be under staged if the muscle is not present in the transurethral resection sample and that repeat resection of a T1 tumor can help greatly in accurate staging. 1‐3 We urologists may be doing our basic science colleagues a disservice by not defining better the actual extent of the cancer used in biological findings.