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

Area of Science:

• Oncology
• Genomics
• Molecular Biology

Background:

• Transforming growth factor beta (TGF-β) signaling is crucial in cellular processes and cancer.
• Dysregulation of TGF-β-Smad signaling contributes to tumorigenesis and metastasis.
• Understanding genomic alterations in this pathway is vital for cancer research.

Purpose of the Study:

• To perform an integromic analysis of gene alterations in TGF-β-Smad signaling across diverse cancer types.
• To identify specific genes and mutation hotspots within the TGF-β superfamily.
• To correlate these alterations with clinical outcomes and molecular features.

Main Methods:

• Analysis of 9,125 tumor samples from The Cancer Genome Atlas (TCGA) across 33 cancer types.
• Integromic analysis focusing on mutations, homozygous deletions, and amplifications of TGF-β signaling genes.
• Correlation analyses including DNA methylation and miRNA expression.

Main Results:

• At least one genomic alteration in TGF-β signaling genes was found in 39% of samples, with highest prevalence in gastrointestinal cancers.
• Mutation hotspots identified in TGF-β ligands (BMP5), receptors (TGFBR2, AVCR2A, BMPR2), and Smads (SMAD2, SMAD4).
• TGF-β superfamily alterations positively correlated with metastasis-associated gene expression and decreased patient survival.

Conclusions:

• Genomic alterations in TGF-β signaling are frequent across multiple cancer types.
• These alterations are linked to aggressive tumor phenotypes and poorer prognosis.
• The findings offer a molecular perspective for future therapeutic strategies targeting TGF-β pathways in cancer.