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

TY - JOUR

T1 - A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-β Superfamily

AU - Korkut, Anil

AU - Zaidi, Sobia

AU - Kanchi, Rupa S

AU - Rao, Shuyun

AU - Gough, Nancy R

AU - Schultz, Andre

AU - Li, Xubin

AU - Lorenzi, Philip L

AU - Berger, Ashton C

AU - Robertson, Gordon

AU - Kwong, Lawrence N

AU - Datto, Mike

AU - Roszik, Jason

AU - Ling, Shiyun

AU - Ravikumar, Visweswaran

AU - Manyam, Ganiraju

AU - Rao, Arvind

AU - Shelley, Simon

AU - Liu, Yuexin

AU - Ju, Zhenlin

AU - Hansel, Donna

AU - de Velasco, Guillermo

AU - Pennathur, Arjun

AU - Andersen, Jesper B

AU - O'Rourke, Colm J

AU - Ohshiro, Kazufumi

AU - Jogunoori, Wilma

AU - Nguyen, Bao-Ngoc

AU - Li, Shulin

AU - Osmanbeyoglu, Hatice U

AU - Ajani, Jaffer A

AU - Mani, Sendurai A

AU - Houseman, Andres

AU - Wiznerowicz, Maciej

AU - Chen, Jian

AU - Gu, Shoujun

AU - Ma, Wencai

AU - Zhang, Jiexin

AU - Tong, Pan

AU - Cherniack, Andrew D

AU - Deng, Chuxia

AU - Resar, Linda

AU - Weinstein, John N

AU - Mishra, Lopa

AU - Akbani, Rehan

AU - Cancer Genome Atlas Research Network

N1 - Copyright © 2018 Elsevier Inc. All rights reserved.

PY - 2018/10/24

Y1 - 2018/10/24

N2 - 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.

AB - 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.

U2 - 10.1016/j.cels.2018.08.010

DO - 10.1016/j.cels.2018.08.010

M3 - Journal article

C2 - 30268436

SN - 2405-4712

VL - 7

SP - 422-437.e1-e7

JO - Cell Systems

JF - Cell Systems

IS - 4

ER -