Prediction of Stage, Grade, and Survival in Bladder Cancer Using Genome-wide Expression Data: A Validation Study

Abstract

Purpose: To evaluate performances of published gene signatures for the assessment of urothelial carcinoma.Experimental Design: We evaluated 28 published gene signatures designed for diagnostic and prognostic purposes of urothelial cancer. The investigated signatures include eight signatures for stage, five for grade, four for progression, and six for survival. We used two algorithms for classification, nearest centroid classification and support vector machine, and Cox regression to evaluate signature performance in four independent data sets.Results: The overlap of genes among the signatures was low, ranging from 11% among stage signatures to 0.6% among survival signatures. The published signatures predicted muscle-invasive and high-grade tumors with accuracies in the range of 70% to 90%. The performance for a given signature varied considerably with the validation data set used, and interestingly, some of the best performing signatures were not designed for the tested classification problem. In addition, several nonbladder-derived gene signatures performed equally well. Large randomly selected gene signatures performed better than the published signatures, and by systematically increasing signature size, we show that signatures with >150 genes are needed to obtain robust performance in independent validation data sets. None of the published survival signatures performed better than random assignments when applied to independent validation data.Conclusion: We conclude that gene expression signatures with >150 genes predict muscle-invasive growth and high-grade tumors with robust accuracies. Special considerations have to be taken when designing gene signatures for outcome in bladder cancer. Clin Cancer Res; 16(17); 4421-33. ©2010 AACR.

Prognostic and Chemotherapy Predictive Value of Gene-Expression Phenotypes in Primary Lung Adenocarcinoma

“…5A, center). These results are consistent with gene signature stability analyses performed by Lauss and colleagues in bladder cancer (34). Next, we evaluated the classification robustness when randomly selecting a subset of samples from a cohort that was subsequently used to re-center the entire cohort before classification.…”

High-grade papillary urothelial carcinoma of the urinary tract: a clinicopathologic analysis of a post–World Health Organization/International Society of Urological Pathology classification cohort from a single academic center

“…In addition, chromosomal alterations and allelic deletions, DNA ploidy, mutations of the fibroblast growth factor receptor-3 gene, activation of H-Ras oncogene, and overexpression of angiogenic-related factors such as vascular endothelial growth factor (VEGF) and matrix metalloproteinases, among others, have been linked to the likelihood of tumor recurrence [19,[21][22][23][24][25]. Recent studies have evaluated the use of genome-wide expression data in predicting outcome in urothelial carcinomas [26,27]. However, further evaluations and external validation studies are required to establish the clinical utility of these exciting molecular assays.…”

Modelling bladder cancer in mice: opportunities and challenges

“…Indeed, certain molecular alterations, such as gain of function mutations of FGFR3 , are prevalent in low-grade non-muscle invasive bladder cancers whereas other alterations, such as p53 loss or mutation, are prevalent in high-grade muscle invasive bladder cancers 53, 59–62 . Although analyses of gene expression profiling 63–68 and/or genomic alterations 65, 69–73 have supported the general concept that low-grade non-invasive versus high-grade invasive bladder tumors are molecularly distinct, it is difficult to fully reconcile a mutual-exclusivity model considering that some superficial bladder tumors can progress to invasive disease. Furthermore, meta-analysis of expression profiling data from non-invasive and invasive bladder cancers failed to identify molecular subtypes that are clearly associated with pathological stage 74 .…”