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

Cancer Genome Atlas Research Network

doi:10.1016/j.cels.2018.08.010

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

Cancer Genome Atlas Research Network

Research output: Contribution to journal › Article › peer-review

108 Citations (Scopus)

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.

Original language	English
Pages (from-to)	422-437.e7
Journal	Cell systems
Volume	7
Issue number	4
DOIs	https://doi.org/10.1016/j.cels.2018.08.010
Publication status	Published - 24 Oct 2018
Externally published	Yes

Keywords

Bone Morphogenetic Protein 5/genetics
DNA Methylation
Humans
MicroRNAs/genetics
Mutation Rate
Neoplasms/genetics
Receptor, Transforming Growth Factor-beta Type I/genetics
Signal Transduction
Smad Proteins/genetics
Transforming Growth Factor beta/genetics

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10.1016/j.cels.2018.08.010

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@article{a85847477f494f138192d4c07a3ac433,

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

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.",

keywords = "Bone Morphogenetic Protein 5/genetics, DNA Methylation, Humans, MicroRNAs/genetics, Mutation Rate, Neoplasms/genetics, Receptor, Transforming Growth Factor-beta Type I/genetics, Signal Transduction, Smad Proteins/genetics, Transforming Growth Factor beta/genetics",

author = "{Cancer Genome Atlas Research Network} and Anil Korkut and Sobia Zaidi and Kanchi, {Rupa S} and Shuyun Rao and Gough, {Nancy R} and Andre Schultz and Xubin Li and Lorenzi, {Philip L} and Berger, {Ashton C} and Gordon Robertson and Kwong, {Lawrence N} and Mike Datto and Jason Roszik and Shiyun Ling and Visweswaran Ravikumar and Ganiraju Manyam and Arvind Rao and Simon Shelley and Yuexin Liu and Zhenlin Ju and Donna Hansel and {de Velasco}, Guillermo and Arjun Pennathur and Andersen, {Jesper B} and O'Rourke, {Colm J} and Kazufumi Ohshiro and Wilma Jogunoori and Bao-Ngoc Nguyen and Shulin Li and Osmanbeyoglu, {Hatice U} and Ajani, {Jaffer A} and Mani, {Sendurai A} and Andres Houseman and Maciej Wiznerowicz and Jian Chen and Shoujun Gu and Wencai Ma and Jiexin Zhang and Pan Tong and Cherniack, {Andrew D} and Chuxia Deng and Linda Resar and Weinstein, {John N} and Lopa Mishra and Rehan Akbani",

year = "2018",

month = oct,

day = "24",

doi = "10.1016/j.cels.2018.08.010",

language = "English",

volume = "7",

pages = "422--437.e7",

journal = "Cell systems",

issn = "2405-4712",

publisher = "Cell Press",

number = "4",

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

AU - Cancer Genome Atlas Research Network

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

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.

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.

KW - Bone Morphogenetic Protein 5/genetics

KW - DNA Methylation

KW - Humans

KW - MicroRNAs/genetics

KW - Mutation Rate

KW - Neoplasms/genetics

KW - Receptor, Transforming Growth Factor-beta Type I/genetics

KW - Signal Transduction

KW - Smad Proteins/genetics

KW - Transforming Growth Factor beta/genetics

UR - http://www.scopus.com/inward/record.url?scp=85055618721&partnerID=8YFLogxK

U2 - 10.1016/j.cels.2018.08.010

DO - 10.1016/j.cels.2018.08.010

M3 - Article

C2 - 30268436

SN - 2405-4712

VL - 7

SP - 422-437.e7

JO - Cell systems

JF - Cell systems

IS - 4

ER -

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

Abstract

Keywords

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