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A pan-cancer analysis reveals high-frequency genetic alterations in mediators of signaling by the TGF-β superfamily

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Title: A pan-cancer analysis reveals high-frequency genetic alterations in mediators of signaling by the TGF-β superfamily
Authors: Korkut, A
Zaidi, S
Kanchi, RS
Rao, S
Gough, NR
Schultz, A
Li, X
Lorenzi, PL
Berger, AC
Robertson, G
Kwong, LN
Datto, M
Roszik, J
Ling, S
Ravikumar, V
Manyam, G
Rao, A
Shelley, S
Liu, Y
Ju, Z
Hansel, D
De Velasco, G
Pennathur, A
Andersen, JB
O'Rourke, CJ
Ohshiro, K
Jogunoori, W
Nguyen, B-N
Li, S
Osmanbeyoglu, HU
Ajani, JA
Mani, SA
Houseman, A
Wiznerowicz, M
Chen, J
Gu, S
Ma, W
Zhang, J
Tong, P
Cherniack, AD
Deng, C
Resar, L
Cancer Genome Atlas Research Network
Weinstein, JN
Mishra, L
Akbani, R
Item Type: Journal Article
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.
Issue Date: 24-Oct-2018
Date of Acceptance: 21-Aug-2018
URI: http://hdl.handle.net/10044/1/71250
DOI: https://dx.doi.org/10.1016/j.cels.2018.08.010
ISSN: 2405-4712
Publisher: Elsevier (Cell Press)
Start Page: 422
End Page: 437.e7
Journal / Book Title: Cell Systems
Volume: 7
Issue: 4
Copyright Statement: ©2018 The Authors. Published by Elsevier Inc.This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Sponsor/Funder: SAIC-F-Frederick, Inc
Leidos Biomedical Research, Inc.
Funder's Grant Number: TCGA Pilot Program
15Y011ST
Keywords: DNA methylation
Pan-Cancer
TCGA
TGF-β
TGF-β pathway
The Cancer Genome Atlas
cancer
microRNA
mutation hotspot
transcription
Cancer Genome Atlas Research Network
DNA methylation
Pan-Cancer
TCGA
TGF-β
TGF-β pathway
The Cancer Genome Atlas
cancer
microRNA
mutation hotspot
transcription
Publication Status: Published
Conference Place: United States
Open Access location: http://www.cell.com/cell-systems/retrieve/pii/S2405471218303570?_returnURL=https:%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2405471218303570%3Fshowall%3Dtrue
Online Publication Date: 2018-09-26
Appears in Collections:Department of Surgery and Cancer