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

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.

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


Cell Syst, 2018, 7 (4)

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