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