Development and Validation of a NanoString BASE47 Classifier for the Molecular Classification of Bladder Cancer - Expert Commentary

The molecular classification of muscle-invasive urothelial cancer (UC) using RNA sequencing (RNAseq) data has confirmed the existence of distinct intrinsic subtypes that vary in their prognosis and response to therapy. The molecular classifier BASE47 (Bladder cancer Analysis of Subtype by gene Expression) uses RNAseq transcriptomic data to differentiate between basal-like and luminal-like subtypes. Although the BASE47 gene expression profiling data could guide clinical decisions, the routine use of these platforms is restricted by cost and technical difficulties.


Kardos and his colleagues recently investigated whether the NanoString-derived BASE47 platform can reproduce the subtyping from the original BASE47 RNAseq promptly and at a lower cost to facilitate using molecular data in clinical practice. The study was published in PLoS ONE. The investigators used formalin-fixed, paraffin-embedded (FFPE) tissues of 115 muscle-invasive urothelial tumors from 3 independent data sets comprising one training and two validation cohorts. Using NanoString's nCounter technology, custom probes were designed to match the 47-classifier gene signature from the BASE47 transcriptomic platform.

Accuracy of the subtype calling improved by applying NanoString-derived RNA classifier on the 52 training tumor samples relative to using transcriptome-derived BASE47 classifier, with a drop of the falsely obtained expression results from 46% to 13% using the former platform (p < 0.001). The validity of the Nanostring BASE47 probe set was reproduced in the two independent validation tumor samples with only two incorrect sample classifications compared to the original transcriptome BASE47 classifier. The expression of individual genes was significantly correlated between both platforms (R = 0.88, p = 0.001). There was no overall survival difference in basal and luminal tumors in this cohort of patients based on their NanoString BASE47 subtype.

The validation of this NanoString derived BASE47 platform overcomes some challenges from using the transcriptome-derived BASE47 classifier. The development of exome capture-based transcriptome-based methods that are suitable for use in formalin-fixed paraffin-embedded tissues could potentially determine molecular base-subtype membership in a clinical setting. These platforms are critical first steps towards precision-based management of muscle-invasive urothelial cancers.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York


References:

  1. Kardos J, Rose TL, Manocha U, Wobker SE, Damrauer JS, Bivalaqua TJ, et al. Development and validation of a NanoString BASE47 bladder cancer gene classifier. PLoS One. 2020;15(12 December):1–16. doi:10.1371/journal.pone.0243935. PMID: 33332422.
  2. Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA. 2006; 295: 2492–2502. doi.org/ 10.1001/jama.295.21.2492. PMID: 16757721.

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