Multilevel Genomics-Based Taxonomy of Renal Cell Carcinoma.

Abstract

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.

• Authors: Fengju Chen, Yiqun Zhang, Yasin Şenbabaoğlu, Giovanni Ciriello, Lixing Yang, Ed Reznik, Brian Shuch, Goran Micevic, Guillermo De Velasco, Eve Shinbrot, Michael S Noble, Yiling Lu, Kyle R Covington, Liu Xi, Jennifer A Drummond, Donna Muzny, Hyojin Kang, Junehawk Lee, Pheroze Tamboli, Victor Reuter, Carl Simon Shelley, Benny A Kaipparettu, Donald P Bottaro, Andrew K Godwin, Richard A Gibbs, Gad Getz, Raju Kucherlapati, Peter J Park, Chris Sander, Elizabeth P Henske, Jane H Zhou, David J Kwiatkowski, Thai H Ho, Toni K Choueiri, James J Hsieh, Rehan Akbani, Gordon B Mills, A Ari Hakimi, David A Wheeler, Chad J Creighton
• Journal: Cell reports (Cell Rep) Vol. 14 Issue 10 Pg. 2476-89 (Mar 15 2016) ISSN: 2211-1247 [Electronic] United States
• PMID: 26947078 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
• Chromatin
• MicroRNAs
• RNA, Messenger
• TFE3 protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors (genetics, metabolism)
• Carcinoma, Renal Cell (genetics, mortality, pathology)
• Chromatin (metabolism)
• Gene Expression Profiling
• Genomics
• Humans
• Kidney Neoplasms (genetics, mortality, pathology)
• MicroRNAs (metabolism)
• Mutation
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA, Messenger (metabolism)
• Signal Transduction (genetics)
• Survival Rate
• TOR Serine-Threonine Kinases (metabolism)