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.
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, B-N; 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
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