Multiplatform Analysis of 12 Cancer Types Reveals Molecular Classification within and across Tissues of Origin

Katherine A. Hoadley^{1, 20}, Christina Yau^{2, 20}, Denise M. Wolf^{3, 20}, Andrew D. Cherniack^{4, 20}, David Tamborero⁵, Sam Ng⁶, Max D.M. Leiserson⁷, Beifang Niu⁸, Michael D. McLellan⁸, Vladislav Uzunangelov⁶, Jiashan Zhang⁹, Cyriac Kandoth⁸, Rehan Akbani¹⁰, Hui Shen^{11, 22}, Larsson Omberg¹², Andy Chu¹³, Adam A. Margolin^{12, 21}, Laura J. van’t Veer³, Nuria Lopez-Bigas^{5, 14}, Peter W. Laird^{11, 22}, Benjamin J. Raphael⁷, Li Ding⁸, A. Gordon Robertson¹³, Lauren A. Byers¹⁰, Gordon B. Mills¹⁰, John N. Weinstein¹⁰, Carter Van Waes¹⁸, Zhong Chen¹⁹, Eric A. Collisson¹⁵,The Cancer Genome Atlas Research Network, Christopher C. Benz^{2, ,} , Charles M. Perou^{1, 16, 17, ,} , Joshua M. Stuart^{6, ,}

¹ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA
² Buck Institute for Research on Aging, Novato, CA 94945, USA
³ Department of Laboratory Medicine, University of California San Francisco, 2340 Sutter St, San Francisco, CA, 94115, USA
⁴ The Eli and Edythe Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
⁵ Research Unit on Biomedical Informatics, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Dr. Aiguader 88, Barcelona 08003, Spain
⁶ Department of Biomolecular Engineering, Center for Biomolecular Sciences and Engineering, University of California, Santa Cruz, 1156 High St., Santa Cruz, CA 95064, USA
⁷ Department of Computer Science and Center for Computational Molecular Biology, Brown University, 115 Waterman St, Providence RI 02912, USA
⁸ The Genome Institute, Washington University, St Louis, MO 63108, USA
⁹ National Cancer Institute, NIH, Bethesda, MD 20892, USA
¹⁰ UT MD Anderson Cancer Center, Bioinformatics and Computational Biology, 1400 Pressler Street, Unit 1410, Houston, TX 77030, USA
¹¹ USC Epigenome Center, University of Southern California Keck School of Medicine, 1450 Biggy Street, Los Angeles, CA 90033, USA
¹² Sage Bionetworks 1100 Fairview Avenue North, M1-C108, Seattle, WA 98109-1024, USA
¹³ Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada
¹⁴ Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluís Companys, 23, Barcelona 08010, Spain
¹⁵ Department of Medicine, University of California San Francisco, 450 35d St, San Francisco, CA, 94148, USA
¹⁶ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA
¹⁷ Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA
¹⁸ Building 10, Room 4-2732, NIDCD/NIH, 10 Center Drive, Bethesda, MD 20892
¹⁹ Head and Neck Surgery Branch, NIDCD/NIH, 10 Center Drive, Room 5D55, Bethesda, MD 20892

Received 23 December 2013, Revised 4 April 2014, Accepted 23 June 2014, Available online 7 August 2014

Summary

Recent genomic analyses of pathologically defined tumor types identify “within-a-tissue” disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head and neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multiplatform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All data sets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies.

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