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

Cell Syst. 2018 Oct 24;7(4):422-437.e7. doi: 10.1016/j.cels.2018.08.010. Epub 2018 Sep 26.

Abstract

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.

Keywords: DNA methylation; Pan-Cancer; TCGA; TGF-β; TGF-β pathway; The Cancer Genome Atlas; cancer; microRNA; mutation hotspot; transcription.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Bone Morphogenetic Protein 5 / genetics
  • Bone Morphogenetic Protein 5 / metabolism
  • DNA Methylation
  • Humans
  • MicroRNAs / genetics
  • Mutation Rate*
  • Neoplasms / genetics*
  • Receptor, Transforming Growth Factor-beta Type I / genetics
  • Receptor, Transforming Growth Factor-beta Type I / metabolism
  • Signal Transduction*
  • Smad Proteins / genetics
  • Smad Proteins / metabolism
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*

Substances

  • BMP5 protein, human
  • Bone Morphogenetic Protein 5
  • MicroRNAs
  • Smad Proteins
  • Transforming Growth Factor beta
  • Receptor, Transforming Growth Factor-beta Type I