W. Rathmell
Last active: 11/27/2019

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

Korkut A, Zaidi S, Kanchi RS, Rao S, Gough NR, Schultz A, Li X, Lorenzi PL, Berger AC, Robertson G, Kwong LN, Datto M, Roszik J, Ling S, Ravikumar V, Manyam G, Rao A, Shelley S, Liu Y, Ju Z, Hansel D, de Velasco G, Pennathur A, Andersen JB, O'Rourke CJ, Ohshiro K, Jogunoori W, Nguyen BN, Li S, Osmanbeyoglu HU, Ajani JA, Mani SA, Houseman A, Wiznerowicz M, Chen J, Gu S, Ma W, Zhang J, Tong P, Cherniack AD, Deng C, Resar L, Cancer Genome Atlas Research Network, Weinstein JN, Mishra L, Akbani R
Cell Syst. 2018 7 (4): 422-437.e7

PMID: 30268436 · PMCID: PMC6370347 · DOI:10.1016/j.cels.2018.08.010

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.

Copyright © 2018 Elsevier Inc. All rights reserved.

MeSH Terms (10)

Bone Morphogenetic Protein 5 DNA Methylation Humans MicroRNAs Mutation Rate Neoplasms Receptor, Transforming Growth Factor-beta Type I Signal Transduction Smad Proteins Transforming Growth Factor beta

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