A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-β Superfamily
cancer; DNA methylation; microRNA; mutation hotspot; Pan-Cancer; TCGA; TGF-β; TGF-β pathway; The Cancer Genome Atlas; transcription
© 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.
Korkut, A., Zaidi, S., Kanchi, R., Rao, S., Gough, N., Schultz, A., Li, X., Lorenzi, P., Berger, A., Robertson, G., Kwong, L., 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, J., O'Rourke, C., Ohshiro, K., Jogunoori, W., Nguyen, B., Li, S., Osmanbeyoglu, H., Ajani, J., Mani, S., & Houseman, A. (2018). A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-β Superfamily. Cell Systems, 7 (4). http://dx.doi.org/10.1016/j.cels.2018.08.010