Gene expression signatures predict outcome in non-muscle-invasive bladder carcinoma: a multicenter validation study.
OBJECTIVE
Clinically useful molecular markers predicting the clinical course of patients diagnosed with non-muscle-invasive bladder cancer are needed to improve treatment outcome. Here, we validated four previously reported gene expression signatures for molecular diagnosis of disease stage and carcinoma in situ (CIS) and for predicting disease recurrence and progression.


METHODS
We analyzed tumors from 404 patients diagnosed with bladder cancer in hospitals in Denmark, Sweden, England, Spain, and France using custom microarrays. Molecular classifications were compared with pathologic diagnosis and clinical outcome.


RESULTS
Classification of disease stage using a 52-gene classifier was found to be highly significantly correlated with pathologic stage (P < 0.001). Furthermore, the classifier added information regarding disease progression of T(a) or T(1) tumors (P < 0.001). The molecular 88-gene progression classifier was highly significantly correlated with progression-free survival (P < 0.001) and cancer-specific survival (P = 0.001). Multivariate Cox regression analysis showed the progression classifier to be an independently significant variable associated with disease progression after adjustment for age, sex, stage, grade, and treatment (hazard ratio, 2.3; P = 0.007). The diagnosis of CIS using a 68-gene classifier showed a highly significant correlation with histopathologic CIS diagnosis (odds ratio, 5.8; P < 0.001) in multivariate logistic regression analysis.


CONCLUSIONS
This multicenter validation study confirms in an independent series the clinical utility of molecular classifiers to predict the outcome of patients initially diagnosed with non-muscle-invasive bladder cancer. This information may be useful to better guide patient treatment.
Dyrskjøt
Lars
L
Molecular Diagnostic Laboratory, Department of Clinical Biochemistry, Aarhus University Hospital, Skejby, Denmark.
Zieger
Karsten
K
Real
Francisco X
FX
Malats
Núria
N
Carrato
Alfredo
A
Hurst
Carolyn
C
Kotwal
Sanjeev
S
Knowles
Margaret
M
Malmström
Per-Uno
PU
de la Torre
Manuel
M
Wester
Kenneth
K
Allory
Yves
Y
Vordos
Dimitri
D
Caillault
Aurélie
A
Radvanyi
François
F
Hein
Anne-Mette K
AM
Jensen
Jens L
JL
Jensen
Klaus M E
KM
Marcussen
Niels
N
Orntoft
Torben F
TF
D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*
D014408:Biomarkers, Tumor