A Molecular Signature in Superficial Bladder Carcinoma Predicts Clinical Outcome

Dyrskjøt, Lars; Zieger, Karsten; Kruhøffer, Mogens; Thykjær, Thomas; Jensen, Jens Ledet; Primdahl, Hanne; Aziz, Natasha; Marcussen, Niels; Møller, Klaus; Ørntoft, Torben F.

doi:10.1016/s0022-5347(05)00865-7

Cited by 28 publications

(33 citation statements)

References 3 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For the validation of the gene signatures, a microarray platform was developed, including probes for the genes comprised in the four expression signatures previously described. Oligonucleotide design, microarray spotting procedure, sample labeling, array hybridization, and scanning were done as previously described (11). Briefly, all classifier genes were represented by one to four 60-mer oligonucleotides spotted in duplicate on CodeLink slides (GE Health Care), and all samples (N = 404) were assayed twice using the microarrays.…”

Section: Methodsmentioning

confidence: 99%

“…In a later study, we identified a gene signature for classifying early-stage bladder tumors according to the presence of surrounding CIS (10). Finally, we have identified a gene signature for predicting disease progression (11). Only few studies have thus far documented a clinical utility of the identified gene expression signatures through large-scale validation in independent tumor series.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Gene Expression Signatures Predict Outcome in Non–Muscle-Invasive Bladder Carcinoma: A Multicenter Validation Study

Dyrskjøt¹,

Zieger

Real

et al. 2007

Clinical Cancer Research

184

147

View full text Add to dashboard Cite

Purpose: 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. Experimental Design: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. Conclusion: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.Bladder cancer is a common malignant disease with 357,000 new cases and 145,000 deaths worldwide annually (1). Its prevalence is 3-to 8-fold higher than its incidence, making bladder cancer one of the most prevalent neoplasms, and hence a major burden for health care systems. The overall causespecific 5-year survival rate is about 65%. The disease presents in two different forms: non -muscle-invasive tumors (stages T a and T 1 ), usually treated with a local, organ-sparing approach, and muscle-invasive cancers (stages T 2 -T 4 ), usually requiring cystectomy if cure is intended.The non -muscle-invasive tumors account for f75% of newly diagnosed cases. A low proportion of patients are cured after tumor resection, but the tumors of more than 60% of these patients recur, and the frequency of recurrences has a significant effect on the patients' quality of life. Some of these patients also develop muscle-invasive tumors over time, the proportion ranging from very low for noninvasive papillary low-grade tumors to up to 60% progression for high-grade submucosa-invasive tumors (2, 3). Clinical risk factors for progression include invasion of the lamina propria, high grade, tumor size, occurrence of carcinoma in situ (CIS), and multiplicity or recurrence of ...

show abstract

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Gene Expression Signatures Predict Outcome in Non–Muscle-Invasive Bladder Carcinoma: A Multicenter Validation Study

Dyrskjøt¹,

Zieger

Real

et al. 2007

Clinical Cancer Research

184

147

View full text Add to dashboard Cite

show abstract

“…Finally, on the subject of independent validation of signatures from their prior microarray studies, Dyrskjot and colleagues recently reported an international multicentre validation study demonstrating the efficacy of their reported signatures of progression of superficial bladder tumours to muscle invasion. 44,46,47 In a small study that investigated prediction of chemotherapeutic sensitivity for bladder cancer, Takata and colleagues profiled tumour response to neoadjuvant MVAC therapy using cDNA microarrays. Fourteen tumours were used to develop a signature of 14 predictive genes.…”

Section: Genome-wide Discovery Of Multiplexed Biomarkersmentioning

confidence: 99%

Personalized medicine in advanced urothelial cancer: when to treat, how to treat and who to treat

Ehdaie

Smith

Theodorescu

2013

CUAJ

View full text Add to dashboard Cite

The past decade has provided an improved understanding of the molecular mechanism of bladder cancer by defining distinct pathways in tumorigenesis and progression. Advances in technologies, such as high-throughput transcript profiling, microarrays and proteomics, offer a systematic approach to identifying targets for bladder cancer diagnostics and drug discovery. This review presents a select outline of the advances in the development of biomarkers and targets for patient prognosis and therapy selection. This paper describes a representative cohort of recent studies that have the potential to significantly impact the management of muscle invasive and metastatic urothelial carcinoma of the bladder. Space constraints do not permit this review to be comprehensive and we apologize to the authors whose work we do not cite.

show abstract

“…Biological material from bladder tumors was obtained directly from surgery and processed as described earlier (Dyrskjot et al, 2005). Informed written consent was obtained from all patients, and research protocols were approved by the scientific ethical committee of Aarhus County.…”

Section: Patient Materialsmentioning

confidence: 99%

miR-145 induces caspase-dependent and -independent cell death in urothelial cancer cell lines with targeting of an expression signature present in Ta bladder tumors

et al. 2009

View full text Add to dashboard Cite

Downregulation of miR-145 in a variety of cancers suggests a possible tumor suppressor function for this microRNA. Here, we show that miR-145 expression is reduced in bladder cancer and urothelial carcinoma in situ, compared with normal urothelium, using transcription profiling and in situ hybridization. Ectopic expression of miR-145 induced extensive apoptosis in urothelial carcinoma cell lines (T24 and SW780) as characterized by caspase activation, nuclear condensation and fragmentation, cellular shrinkage, and detachment. However, cell death also proceeded upon caspase inhibition by the pharmacological inhibitor zVAD-fmk and ectopic expression of anti-apoptotic Bcl-2, indicating the activation of an alternative caspase-independent death pathway. Microarray analysis of transcript levels in T24 cells, before the onset of cell death, showed destabilization of mRNAs enriched for miR-145 7mer target sites. Among these, direct targeting of CBFB, PPP3CA, and CLINT1 was confirmed by a luciferase reporter assay. Notably, a 22-gene signature targeted on enforced miR-145 expression in T24 cells was significantly (Po0.00003) upregulated in 55 Ta bladder tumors with concomitant reduction of miR-145. Our data indicate that reduction in miR-145 expression may provide bladder cancer cells with a selective advantage by inhibition of cell death otherwise triggered in malignant cells.

show abstract

A Molecular Signature in Superficial Bladder Carcinoma Predicts Clinical Outcome

Cited by 28 publications

References 3 publications

Gene Expression Signatures Predict Outcome in Non–Muscle-Invasive Bladder Carcinoma: A Multicenter Validation Study

Gene Expression Signatures Predict Outcome in Non–Muscle-Invasive Bladder Carcinoma: A Multicenter Validation Study

Personalized medicine in advanced urothelial cancer: when to treat, how to treat and who to treat

miR-145 induces caspase-dependent and -independent cell death in urothelial cancer cell lines with targeting of an expression signature present in Ta bladder tumors

Contact Info

Product

Resources

About