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

Cell Syst
Authors
Keywords
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.

Year of Publication
2018
Journal
Cell Syst
Volume
7
Issue
4
Pages
422-437.e7
Date Published
2018 10 24
ISSN
2405-4712
DOI
10.1016/j.cels.2018.08.010
PubMed ID
30268436
PubMed Central ID
PMC6370347
Links
Grant list
U01 CA230690 / CA / NCI NIH HHS / United States
P30 CA016672 / CA / NCI NIH HHS / United States
U24 CA143866 / CA / NCI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
U24 CA143840 / CA / NCI NIH HHS / United States
U24 CA143843 / CA / NCI NIH HHS / United States
U24 CA143848 / CA / NCI NIH HHS / United States
R01 CA183793 / CA / NCI NIH HHS / United States
U24 CA143883 / CA / NCI NIH HHS / United States
U24 CA143882 / CA / NCI NIH HHS / United States
P01 CA130821 / CA / NCI NIH HHS / United States
R01 DK102943 / DK / NIDDK NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
U24 CA143835 / CA / NCI NIH HHS / United States
R01 AA023146 / AA / NIAAA NIH HHS / United States
P30 CA006973 / CA / NCI NIH HHS / United States
U24 CA210950 / CA / NCI NIH HHS / United States
U24 CA143845 / CA / NCI NIH HHS / United States
U24 CA143799 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
U24 CA144025 / CA / NCI NIH HHS / United States
U24 CA143858 / CA / NCI NIH HHS / United States
R01 CA236591 / CA / NCI NIH HHS / United States
I01 BX003732 / BX / BLRD VA / United States
U54 HG003079 / HG / NHGRI NIH HHS / United States
R00 CA207871 / CA / NCI NIH HHS / United States
U24 CA210949 / CA / NCI NIH HHS / United States
R01 CA232741 / CA / NCI NIH HHS / United States
U24 CA143867 / CA / NCI NIH HHS / United States
U24 CA199461 / CA / NCI NIH HHS / United States