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

Abstract

SUMMARY 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, BMPR2), and Smads (SMAD2, 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.

Immunomodulatory TGF-β Signaling in Hepatocellular Carcinoma

“…Genomic alterations in the TGF-b signaling pathway, including somatic mutation, homozygous deletion, or amplification, were found in 39% of 9125 tumor samples across 33 cancer types in The Cancer Genome Atlas (TCGA) [32]. Alterations in the TGF-b superfamily correlated with decreased survival [17].…”

An integrative pan-cancer investigation reveals common genetic and transcriptional alterations of AMPK pathway genes as important predictors of clinical outcomes across major cancer types

“…Moreover, the complexity of human cancers is not accurately modeled in animals; less than 8% of results from animal models are translated to clinical trials (27). Despite analyses on tumor genetic datasets providing mostly correlative outcomes, they remain valuable in understanding diseasespecific molecular pathology when interrogated at scale on large patient groups (28), and when results are considered in relation to those obtained from cell lines and animal models.…”

Identification of differentially expressed genes and functional annotations associated with metastases of the uveal melanoma

“…Spectrin beta nonerythrocytic 1 ( SPTBN1 ), an encoding adaptor protein gene, is highly associated with transforming growth factor‐beta (TGF‐β) signaling . TGF‐β has been used to treat metastatic UVM and has achieved long survivals .…”

“…Spectrin beta nonerythrocytic 1 (SPTBN1), an encoding adaptor protein gene, is highly associated with transforming growth factor-beta (TGF-β) signaling. 35 TGF-β has been used to treat metastatic UVM and has achieved long survivals. 36 Another study found that TGF-β stimulates tissue-type plasminogen activator, an enzyme that promotes metastasis by facilitating regression of extracellular matrix.…”