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

• Published in: Cell systems Vol. 7; no. 4; pp. 422 - 437.e7
• Main Authors: Rao, Shuyun, Gough, Nancy R., Roszik, Jason, Ravikumar, Visweswaran, Ohshiro, Kazufumi, Nguyen, Bao-Ngoc, Ajani, Jaffer A., Wiznerowicz, Maciej, Wu, Ye, Liu, Yuexin, Kanchi, Rupa S., Zhang, Jiexin, Gross, Benjamin E., Kundra, Ritika, Phillips, Sarah M., Zhang, Hongxin, Peto, Myron, Mungall, Andrew J., Lai, Phillip H., Van Den Berg, David J., Bodenheimer, Tom, Simons, Janae V., Veluvolu, Umadevi, Fan, Huihui, Bellair, Michelle, Dinh, Huyen, Doddapaneni, HarshaVardhan, Han, Yi, Lee, Sandra, Li, Wei, Mardis, Elaine R., Gastier-Foster, Julie M., Lichtenberg, Tara M., Le, Xuan, Thorp, Richard, Lyadov, Vladimir, De Rose, Agostino, Rabeno, Brenda, Têtu, Bernard, Chabot, John, Hibshoosh, Hanina, Potapova, Olga, Mariani, Odette, Bigner, Darell, Stoop, Hans, Cuppini, Lucia, Finocchiaro, Gaetano, Murawa, Dawid, Guillermo, Armando López, Akeredolu, Teniola, Birrer, Michael, Nagorney, David, Stanton, Melissa, Yang, Ju Dong, Angulo Gonzalez, Ana Maria, Bondaruk, Jolanta, Broaddus, Russell, Guo, Charles, Lazar, Alexander J., Meric-Bernstam, Funda, Tsao, Anne, Carter, Candace, Haydu, Lauren, Hersey, Peter, Stretch, Jonathan, Synott, Maria, Drwiega, Paul, Hung, Nguyen Phi, Kebebew, Electron, Metwalli, Adam R., Schmidt, Laura S., Cernat, Mircea, Gorincioi, Ghenadie, Tamakawa, Raina, Chevalier, Simone, McKercher, Ginette, Smolenski, Kathy, Alvaro, Domenico, Bragazzi, Maria Consiglia, Cardinale, Vincenzo, Chesla, David, Cottingham, Sandra, Lehman, Norman L., Powers, James, Huland, Hartwig, Sauter, Guido, Carroll, Peter R., Forgie, Ian, Carney, Michael, Knutson, Tina, Godwin, Andrew K., Boussioutas, Alex, Saad, Fred, Bocklage, Therese, Feldman, Michael, Valdivieso, Federico, Dhir, Rajiv, Sankarankuty, Ajith, Fantacone-Campbell, J. Leigh, Rubin, Mark A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.10.2018
• Subjects: Bone Morphogenetic Protein 5 - genetics; Bone Morphogenetic Protein 5 - metabolism; cancer; DNA Methylation; Humans; microRNA; MicroRNAs - genetics; mutation hotspot; Mutation Rate; Neoplasms - genetics; Pan-Cancer; Receptor, Transforming Growth Factor-beta Type I - genetics; Receptor, Transforming Growth Factor-beta Type I - metabolism; Signal Transduction; Smad Proteins - genetics; Smad Proteins - metabolism; TCGA; TGF-β; TGF-β pathway; The Cancer Genome Atlas; transcription; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; TGF-β pathway; transcription; DNA methylation; TGF-β; microRNA; cancer; Pan-Cancer; mutation hotspot; TCGA; The Cancer Genome Atlas
• ISSN: 2405-4712; 2405-4720
• 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. [Display omitted] •Genetic alterations in TGF-β pathway members observed in 39% of TCGA cases•GI cancers enriched with hotspot mutations in TGF-β pathway members•Gene alterations correlated with expression of metastasis genes and poor prognosis•TGF-β signaling silenced by miRNAs or DNA methylation in hematologic cancers 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.