Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology
Edited by William G. Kaelin, Jr., Harvard Medical School, Boston, MA, and approved January 15, 2014 (received for review October 2, 2013)
Significance
The identification of molecular subtype heterogeneity in breast cancer has allowed a deeper understanding of breast cancer biology. We present evidence that there are two intrinsic subtypes of high-grade bladder cancer, basal-like and luminal, which reflect the hallmarks of breast biology. Moreover, we have developed an accurate gene set predictor of molecular subtype, the BASE47, that should allow the incorporation of subtype stratification into clinical trials. Further clinical, etiologic, and therapeutic response associations will be of interest in future investigations.
Abstract
We sought to define whether there are intrinsic molecular subtypes of high-grade bladder cancer. Consensus clustering performed on gene expression data from a meta-dataset of high-grade, muscle-invasive bladder tumors identified two intrinsic, molecular subsets of high-grade bladder cancer, termed “luminal” and “basal-like,” which have characteristics of different stages of urothelial differentiation, reflect the luminal and basal-like molecular subtypes of breast cancer, and have clinically meaningful differences in outcome. A gene set predictor, bladder cancer analysis of subtypes by gene expression (BASE47) was defined by prediction analysis of microarrays (PAM) and accurately classifies the subtypes. Our data demonstrate that there are at least two molecularly and clinically distinct subtypes of high-grade bladder cancer and validate the BASE47 as a subtype predictor. Future studies exploring the predictive value of the BASE47 subtypes for standard of care bladder cancer therapies, as well as novel subtype-specific therapies, will be of interest.
Acknowledgments
We thank the members of the W.Y.K. and Perou laboratories, as well as Matthew Wilkerson, for useful discussions. We also thank Dr. Keith Chan for sharing his bladder TIC gene signature. This work was supported by National Institutes of Health Grant R01 CA142794 (to W.Y.K.), T32-CA009688 (to C.J.T.), and Integrative Vascular Biology Training Grant T32-HL069768 (to J.S.D.). W.Y.K. is a Damon Runyon Merck Clinical Investigator.
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Cover image: Pictured is an artist's rendition of a stream of nanoparticles attacking a blood vessel that feeds a tumor (maroon mass at bottom right). Julia Voigt et al. constructed lipid nanoparticles bearing aromatic sulfonate-containing polymers on their surfaces that are preferentially taken up by the endothelial cells of blood vessels. The study demonstrates a potential mechanism to deliver therapeutics directly to tumors by using nanoparticles that target blood vessels. See the article by Voigt et al. on pages 2942–2947. Image courtesy of Robert Schütze, Julia Voigt, and V. Prasad Shastri.
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Published online: February 11, 2014
Published in issue: February 25, 2014
Acknowledgments
We thank the members of the W.Y.K. and Perou laboratories, as well as Matthew Wilkerson, for useful discussions. We also thank Dr. Keith Chan for sharing his bladder TIC gene signature. This work was supported by National Institutes of Health Grant R01 CA142794 (to W.Y.K.), T32-CA009688 (to C.J.T.), and Integrative Vascular Biology Training Grant T32-HL069768 (to J.S.D.). W.Y.K. is a Damon Runyon Merck Clinical Investigator.
Notes
*This Direct Submission article had a prearranged editor.
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Competing Interests
Conflict of interest statement: J.S.D. and W.Y.K. have submitted a patent application for the BASE47 gene classifier.
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