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