Cell Reports
Volume 14, Issue 10, 15 March 2016, Pages 2476-2489
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Article
Multilevel Genomics-Based Taxonomy of Renal Cell Carcinoma

https://doi.org/10.1016/j.celrep.2016.02.024Get rights and content
Under a Creative Commons license
open access

Highlights

  • Comprehensive molecular analysis of 894 primary renal cell carcinomas

  • Nine subtypes defined by systematic analysis of five genomic data platforms

  • Substantial molecular diversity represented within each major histologic type

  • Presumed actionable alterations include PI3K and immune checkpoint pathways

Summary

On the basis of multidimensional and comprehensive molecular characterization (including DNA methalylation and copy number, RNA, and protein expression), we classified 894 renal cell carcinomas (RCCs) of various histologic types into nine major genomic subtypes. Site of origin within the nephron was one major determinant in the classification, reflecting differences among clear cell, chromophobe, and papillary RCC. Widespread molecular changes associated with TFE3 gene fusion or chromatin modifier genes were present within a specific subtype and spanned multiple subtypes. Differences in patient survival and in alteration of specific pathways (including hypoxia, metabolism, MAP kinase, NRF2-ARE, Hippo, immune checkpoint, and PI3K/AKT/mTOR) could further distinguish the subtypes. Immune checkpoint markers and molecular signatures of T cell infiltrates were both highest in the subtype associated with aggressive clear cell RCC. Differences between the genomic subtypes suggest that therapeutic strategies could be tailored to each RCC disease subset.

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This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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Co-first author