Original articleThe role of microRNA profiling in prognosticating progression in Ta and T1 urinary bladder cancer
Introduction
Patients with non–muscle invasive tumors constitute the majority of newly diagnosed cases of urinary bladder cancer. The most frequent form is of the stage Ta category, with a high risk of recurrence but the risk of developing higher stage is small. On the contrary, category T1 tumors have a higher probability of developing higher stage. We have earlier questioned the term progression for category T1 tumors and proposed the term upstaging as these tumors initially have proven infiltrative capacity [1]. For Ta tumors, the term progression seems adequate as this signals a change in tumor biology. Predicting progression/upstaging is difficult with standard clinical criteria. Risk scores and nomograms have been proposed to aid in the prognostication but external validations have not shown an ideal agreement [2]. Thus uncertainty remains in the individual case and search for suitable biomarkers for this purpose have attracted much interest.
MicroRNAs, variants of small noncoding RNAs, have a key function in gene regulation at the epigenetic level [3], [4]. The primary microRNA transcripts are processed by the ribonucleases, Drosha and Dicer, into mature microRNAs. The effect of microRNA on gene expression is due to messenger RNA degradation or alteration in the translational activity caused by microRNA binding to the 3′ or 5′ untranslated regions or the open reading frame of the messenger RNA target [3], [4]. Currently, there are about 2,000 human microRNAs known, regulating most likely up to 60% of the human genome [5]. Oncomirs, microRNAs deregulated in cancer, act either as tumor suppressors or as oncogenes, depending on the target genes affected [3], [4]. For instance, loss of the tumor suppressor microRNA let-7 causes overexpression of the oncogenes RAS, MYC, and HMGA2 in breast and lung cancers [6], [7]. Whereas mir-21, with an oncogenic role, is up-regulated in several cancers targeting tumor suppressor genes such as phosphatase and tensin homolog [4]. MicroRNAs can differentiate between different tumor types and are being used as diagnostic biomarkers for identifying tissue origin in metastatic tumors [8], [9], [10], [11], [12], [13]. In several malignancies, microRNAs are also promising prognostic markers and novel therapeutic targets or compounds [4], [6], [7], [14], [15].
In bladder cancer carcinogenesis, an extensive number of oncomirs have been described to be of importance [16], [17], e.g., microRNAs successfully separating normal urothelium from bladder cancer or representing a specific tumor stage or grade [18], [19], [20], [21], [22], [23], [24]. In low-grade non–muscle invasive tumors, commonly harboring FGFR3 mutations, 7 microRNAs potentially targeting FGFR3 were down-regulated. Reduced levels of 2 of the microRNAs, miR-99a and miR-100, resulted in up-regulation of FGFR3 protein in in vitro studies [18]. In addition, miR-10a-5p and mir-7 are associated with FGFR3 mutation status in Ta tumors [24]. Mutations in p53 are characteristic for invasive bladder cancer, and miR-21, miR-125b, miR-143, miR-30a/c, and miR-223 predicted to target p53 were reported in bladder cancer [16], [18].
Previously, microRNAs predicting disease progression to muscle invasion in non–muscle invasive bladder cancer (Ta and T1) have been reported [19], [25]. In the study by Rosenberg et al., microdissection and examination of both tumor and stromal/muscle compartments were used to exclude microRNAs deriving from the nontumor components. As Ta progression into muscle is a rare event, Ta is often studied together with T1 tumors regarding progression and consequently the definition under these circumstances has to be that of developing muscle-invasive stages. With a close follow-up, the transition of Ta tumor into category T1 can be diagnosed and the management is usually changed accordingly with the intent to stop growth into muscle. Our aim was also to consider this early step of the progression and this has, to our knowledge, not been analyzed before in bladder cancer regarding tumor markers. Specifically, we analyzed microRNA status in tumor specimens from the initial diagnosis and compared that with a control group with stable disease.
Section snippets
Patients and samples
From a prospective database of patients operated for bladder cancer between 1975 and 2002 at the department of Urology, Uppsala University Hospital, those with initially category Ta and T1 disease in whom progressive disease developed and with available tumor tissue were selected as cases. Progression was defined as developing a higher stage during follow-up. A cohort of patients with identical stages registered in the same time frame with no recurrence or recurrence with the same stage served
Results
Quality control consisted of analysis of 2 samples obtained concurrently from the same patient that showed similar profiles (data not shown). A category comparison between Ta and T1 tumors revealed that many microRNAs were significantly different in expression (Fig. 2).
Discussion
This study is different from those previously reported in several aspects. The definition of progression/upstaging comprises all steps of higher stage as opposed to other studies which disregard the Ta to T1 transition. In accordance with the recent study by Rosenberg et al. [25], our method covers more microRNAs than previously assessed in this cancer, uses microdissection, and excludes nontumor microRNAs. A limitation in our study is the relatively small patient material because of
Acknowledgments
We are grateful for the reference pathology of the tumor material from all study cases performed by pathologists Christer Busch and Tina B. Edmonston.
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