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.

  • 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
PubMed ID
Appears In
Cell Syst, 2018, 7 (4)