Abstract
BackgroundCarcinoma in situ (CIS) is believed to be a precursor of invasive bladder cancer. Identification of CIS is a valuable prognostic factor since radical treatment strategies can be offered these patients before the disease becomes invasive.MethodsWe developed a pathway based classifier approach to predict presence or absence of CIS in patients suffering from non muscle invasive bladder cancer. From Ingenuity Pathway Analysis we considered four canonical signalling pathways (p38 MAPK, FGF, Calcium, and cAMP pathways) with most coherent expression of transcription factors (TFs) across samples in a set of twenty-eight non muscle invasive bladder carcinomas. These pathways contained twelve TFs in total. We used the expression of the TFs to predict presence or absence of CIS in a Leave-One-Out Cross Validation classification.ResultsWe showed that TF expression levels in three pathways (FGF, p38 MAPK, and calcium signalling) or the expression of the twelve TFs together could be used to predict presence or absence of concomitant CIS. A cluster analysis based on expression of the twelve TFs separated the samples in two main clusters: one branch contained 11 of the 15 patients without concomitant CIS and with the majority of the genes being down regulated; the other branch contained 10 of 13 patients with concomitant CIS, and here genes were mostly up regulated. The expression in the CIS group was comparable to the expression of twenty-three patients suffering from muscle-invasive bladder carcinoma. Finally, we validated our results in an independent test set and found that prediction of CIS status was possible using TF expression of the p38 MAPK pathway.ConclusionWe conclude that it is possible to use pathway analysis for molecular classification of bladder tumors.
Highlights
Carcinoma in situ (CIS) is believed to be a precursor of invasive bladder cancer
We used the canonical signalling pathways included in Ingenuity Pathway Analysis (IPA) and defined the Transcription Factor Group Correlation Score (TF.GCS) based on Pearson correlations calculated from expression values of the transcription factors (TFs) in the canonical pathways
For three of the four pathways we were able to classify the samples according to CIS status significantly: Calcium signalling (Fisher's Exact Test, p = 0.02); FGF signalling (Fisher's Exact Test, p = 0.0004); and p38 mitogen activated protein kinase (MAPK) signalling (Fisher's Exact Test, p = 0.0056)
Summary
Carcinoma in situ (CIS) is believed to be a precursor of invasive bladder cancer. It is believed that bladder tumors develop through at least two distinct genetic pathways: A low grade form and a high grade form often associated with concomitant CIS. The low grade form is frequently associated with loss-ofheterozygocity (LOH) in chromosome 9 and activating mutation of the FGF receptor 3 (FGFR3). These tumors often recur but seldom progress to an invasive stage. The high grade form is characterised by TP53 gene inactivation and progression to a muscle invasive stage seems to require a subsequent loss of chromosome 9 [3]. CIS is believed to be a precursor of muscle invasive cancers [3,4,5]
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