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

Overview

Journal Cell Syst

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2018 Oct 1

PMID 30268436

Citations 104

Authors

Anil Korkut

Sobia Zaidi

Rupa S Kanchi

Shuyun Rao

Nancy R Gough

Andre Schultz

Xubin Li

Philip L Lorenzi

Ashton C Berger

Gordon Robertson

Lawrence N Kwong

Mike Datto

Jason Roszik

Shiyun Ling

Visweswaran Ravikumar

Ganiraju Manyam

Arvind Rao

Simon Shelley

Yuexin Liu

Zhenlin Ju

Donna Hansel

Guillermo de Velasco

Arjun Pennathur

Jesper B Andersen

Colm J ORourke

Kazufumi Ohshiro

Wilma Jogunoori

Bao-Ngoc Nguyen

Shulin Li

Hatice U Osmanbeyoglu

Jaffer A Ajani

Sendurai A Mani

Andres Houseman

Maciej Wiznerowicz

Jian Chen

Shoujun Gu

Wencai Ma

Jiexin Zhang

Pan Tong

Andrew D Cherniack

Chuxia Deng

Linda Resar

John N Weinstein

Lopa Mishra

Rehan Akbani

Affiliations

Soon will be listed here.

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.

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