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Bioinformatic identification of FGF, p38-MAPK, and calcium signalling pathways associated with carcinoma in situ in the urinary bladder.

Herbsleb M, Christensen OF, Thykjaer T, Wiuf C, Borre M, Orntoft TF, Dyrskjøt L - BMC Cancer (2008)

Bottom Line: 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.We conclude that it is possible to use pathway analysis for molecular classification of bladder tumors.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Diagnostic Laboratory, Aarhus University Hospital Skejby, Brendstrupgaardsvej 100, DK-8200 Aarhus N, Denmark. herbsleb@ki.au.dk

ABSTRACT

Background: Carcinoma 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.

Methods: We 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.

Results: We 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.

Conclusion: We conclude that it is possible to use pathway analysis for molecular classification of bladder tumors.

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Related in: MedlinePlus

Heatmap illustrating the expression level of the twelve transcription factors (rows) found in the four signalling pathways: FGF, p38 MAPK, cAMP and calcium. The columns contain expression of the 15 patients without CIS, 13 patients with adjacent CIS and 23 patients with muscle invasive bladder carcinoma, mTCC. Up regulated genes are yellow, down regulated genes are blue, while black indicates no change with no CIS samples as reference. The colour bar indicates the clinical diagnosis, green, CIS; orange, no CIS, gray, muscle invasive tumors.
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Figure 5: Heatmap illustrating the expression level of the twelve transcription factors (rows) found in the four signalling pathways: FGF, p38 MAPK, cAMP and calcium. The columns contain expression of the 15 patients without CIS, 13 patients with adjacent CIS and 23 patients with muscle invasive bladder carcinoma, mTCC. Up regulated genes are yellow, down regulated genes are blue, while black indicates no change with no CIS samples as reference. The colour bar indicates the clinical diagnosis, green, CIS; orange, no CIS, gray, muscle invasive tumors.

Mentions: We next investigated whether the pathway regulations identified in the tumors with concomitant CIS were comparable to the pathway regulations identified in patients with muscle invasive bladder tumors. Figure 5 shows the expression of the twelve TFs in tumors with and without concomitant CIS and in muscle-invasive tumours (23 patients). The expression of seven of the twelve genes was significantly different when comparing the non muscle invasive tumors without concomitant CIS to both the tumor with concomitant CIS and to the muscle invasive tumors (t-test, ATF2, p-value = 1.2E-4; CREBBP, p-value = 1.2E-2; MEF2A, p-value = 1.7E-4; MEF2C, p-value = 1.7E-3; ATF1, p-value = 2.6E-2; STAT1, p-value = 1.3E-4; STAT3, p-value = 1.2E-2). A hierarchical cluster analysis based on the seven genes significantly separated the patients according to the groups no CIS and CIS/Invasive (χ2-test, p < 2.0E-5). This result indicated that the tumors with concomitant CIS showed an expression similar to the expression found in muscle invasive tumors for the majority of the twelve selected TFs. This is comparable to the large similarities previously found [6].


Bioinformatic identification of FGF, p38-MAPK, and calcium signalling pathways associated with carcinoma in situ in the urinary bladder.

Herbsleb M, Christensen OF, Thykjaer T, Wiuf C, Borre M, Orntoft TF, Dyrskjøt L - BMC Cancer (2008)

Heatmap illustrating the expression level of the twelve transcription factors (rows) found in the four signalling pathways: FGF, p38 MAPK, cAMP and calcium. The columns contain expression of the 15 patients without CIS, 13 patients with adjacent CIS and 23 patients with muscle invasive bladder carcinoma, mTCC. Up regulated genes are yellow, down regulated genes are blue, while black indicates no change with no CIS samples as reference. The colour bar indicates the clinical diagnosis, green, CIS; orange, no CIS, gray, muscle invasive tumors.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2268699&req=5

Figure 5: Heatmap illustrating the expression level of the twelve transcription factors (rows) found in the four signalling pathways: FGF, p38 MAPK, cAMP and calcium. The columns contain expression of the 15 patients without CIS, 13 patients with adjacent CIS and 23 patients with muscle invasive bladder carcinoma, mTCC. Up regulated genes are yellow, down regulated genes are blue, while black indicates no change with no CIS samples as reference. The colour bar indicates the clinical diagnosis, green, CIS; orange, no CIS, gray, muscle invasive tumors.
Mentions: We next investigated whether the pathway regulations identified in the tumors with concomitant CIS were comparable to the pathway regulations identified in patients with muscle invasive bladder tumors. Figure 5 shows the expression of the twelve TFs in tumors with and without concomitant CIS and in muscle-invasive tumours (23 patients). The expression of seven of the twelve genes was significantly different when comparing the non muscle invasive tumors without concomitant CIS to both the tumor with concomitant CIS and to the muscle invasive tumors (t-test, ATF2, p-value = 1.2E-4; CREBBP, p-value = 1.2E-2; MEF2A, p-value = 1.7E-4; MEF2C, p-value = 1.7E-3; ATF1, p-value = 2.6E-2; STAT1, p-value = 1.3E-4; STAT3, p-value = 1.2E-2). A hierarchical cluster analysis based on the seven genes significantly separated the patients according to the groups no CIS and CIS/Invasive (χ2-test, p < 2.0E-5). This result indicated that the tumors with concomitant CIS showed an expression similar to the expression found in muscle invasive tumors for the majority of the twelve selected TFs. This is comparable to the large similarities previously found [6].

Bottom Line: 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.We conclude that it is possible to use pathway analysis for molecular classification of bladder tumors.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Diagnostic Laboratory, Aarhus University Hospital Skejby, Brendstrupgaardsvej 100, DK-8200 Aarhus N, Denmark. herbsleb@ki.au.dk

ABSTRACT

Background: Carcinoma 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.

Methods: We 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.

Results: We 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.

Conclusion: We conclude that it is possible to use pathway analysis for molecular classification of bladder tumors.

Show MeSH
Related in: MedlinePlus