A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-β Superfamily

Anil Korkut, University of Texas MD Anderson Cancer Center
Sobia Zaidi, The George Washington University
Rupa S. Kanchi, University of Texas MD Anderson Cancer Center
Shuyun Rao, The George Washington University
Nancy R. Gough, The George Washington University
Andre Schultz, University of Texas MD Anderson Cancer Center
Xubin Li, University of Texas MD Anderson Cancer Center
Philip L. Lorenzi, University of Texas MD Anderson Cancer Center
Ashton C. Berger, Massachusetts Institute of Technology
Gordon Robertson, British Columbia Cancer Agency
Lawrence N. Kwong, University of Texas MD Anderson Cancer Center
Mike Datto, Duke University School of Medicine
Jason Roszik, University of Texas MD Anderson Cancer Center
Shiyun Ling, University of Texas MD Anderson Cancer Center
Visweswaran Ravikumar, University of Texas MD Anderson Cancer Center
Ganiraju Manyam, University of Texas MD Anderson Cancer Center
Arvind Rao, University of Texas MD Anderson Cancer Center
Simon Shelley, University of Wisconsin School of Medicine and Public Health
Yuexin Liu, University of Texas MD Anderson Cancer Center
Zhenlin Ju, University of Texas MD Anderson Cancer Center
Donna Hansel, University of California, San Diego
Guillermo de Velasco, Dana-Farber Cancer Institute
Arjun Pennathur, University of Pittsburgh School of Medicine
Jesper B. Andersen, Biotech Research & Innovation Centre
Colm J. O'Rourke, Biotech Research & Innovation Centre
Kazufumi Ohshiro, The George Washington University
Wilma Jogunoori, The George Washington University
Bao Ngoc Nguyen, The George Washington University
Shulin Li, University of Texas MD Anderson Cancer Center
Hatice U. Osmanbeyoglu, Memorial Sloan-Kettering Cancer Center
Jaffer A. Ajani, University of Texas MD Anderson Cancer Center
Sendurai A. Mani, University of Texas MD Anderson Cancer Center
Andres Houseman, Oregon State University

Document Type

Journal Article

Publication Date

10-24-2018

Journal

Cell Systems

Volume

7

Issue

4

DOI

10.1016/j.cels.2018.08.010

Keywords

cancer; DNA methylation; microRNA; mutation hotspot; Pan-Cancer; TCGA; TGF-β; TGF-β pathway; The Cancer Genome Atlas; transcription

Abstract

© 2018 Elsevier Inc. We present an integromic analysis of gene alterations that modulate transforming growth factor β (TGF-β)-Smad-mediated signaling in 9,125 tumor samples across 33 cancer types in The Cancer Genome Atlas (TCGA). Focusing on genes that encode mediators and regulators of TGF-β signaling, we found at least one genomic alteration (mutation, homozygous deletion, or amplification) in 39% of samples, with highest frequencies in gastrointestinal cancers. We identified mutation hotspots in genes that encode TGF-β ligands (BMP5), receptors (TGFBR2, AVCR2A, and BMPR2), and Smads (SMAD2 and SMAD4). Alterations in the TGF-β superfamily correlated positively with expression of metastasis-associated genes and with decreased survival. Correlation analyses showed the contributions of mutation, amplification, deletion, DNA methylation, and miRNA expression to transcriptional activity of TGF-β signaling in each cancer type. This study provides a broad molecular perspective relevant for future functional and therapeutic studies of the diverse cancer pathways mediated by the TGF-β superfamily. To date, there are no studies of the TGF-β superfamily of signaling pathways across multiple cancers. This study represents a key starting point for unraveling the role of this complex superfamily in 33 divergent cancer types from over 9,000 patients.

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