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

The Cancer Genome Atlas Research Network

Research output: Contribution to journalArticle

6 Citations (Scopus)

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. 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.

Original languageEnglish (US)
Pages (from-to)422-437.e7
JournalCell Systems
Volume7
Issue number4
DOIs
StatePublished - Oct 24 2018

Fingerprint

Transforming Growth Factors
Neoplasms
Sequence Deletion
Genes
Gastrointestinal Neoplasms
Atlases
DNA Methylation
MicroRNAs
Genome
Neoplasm Metastasis
Ligands
Mutation
Survival

Keywords

  • cancer
  • DNA methylation
  • microRNA
  • mutation hotspot
  • Pan-Cancer
  • TCGA
  • TGF-β
  • TGF-β pathway
  • The Cancer Genome Atlas
  • transcription

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Histology
  • Cell Biology

Cite this

A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-β Superfamily. / The Cancer Genome Atlas Research Network.

In: Cell Systems, Vol. 7, No. 4, 24.10.2018, p. 422-437.e7.

Research output: Contribution to journalArticle

The Cancer Genome Atlas Research Network. / A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-β Superfamily. In: Cell Systems. 2018 ; Vol. 7, No. 4. pp. 422-437.e7.
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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. 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.",
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AU - Ma, Wencai

AU - Zhang, Jiexin

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AU - Cherniack, Andrew D.

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KW - DNA methylation

KW - microRNA

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KW - Pan-Cancer

KW - TCGA

KW - TGF-β

KW - TGF-β pathway

KW - The Cancer Genome Atlas

KW - transcription

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