Rearrangement-mediated cis-regulatory alterations in advanced patient tumors reveal interactions with therapy
Yiqun Zhang,
Fengju Chen,
Erin Pleasance,
Laura Williamson,
Cameron J. Grisdale,
Emma Titmuss,
Janessa Laskin,
Steven J.M. Jones,
Isidro Cortes-Ciriano,
Marco A. Marra,
Chad J. Creighton
Affiliations
Yiqun Zhang
Division of Biostatistics, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
Fengju Chen
Division of Biostatistics, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
Erin Pleasance
Canada’s Michael Smith Genome Sciences Centre at BC Cancer, Vancouver, British Columbia, Canada
Laura Williamson
Canada’s Michael Smith Genome Sciences Centre at BC Cancer, Vancouver, British Columbia, Canada
Cameron J. Grisdale
Canada’s Michael Smith Genome Sciences Centre at BC Cancer, Vancouver, British Columbia, Canada
Emma Titmuss
Canada’s Michael Smith Genome Sciences Centre at BC Cancer, Vancouver, British Columbia, Canada
Janessa Laskin
Department of Medical Oncology, BC Cancer, Vancouver, British Columbia, Canada
Steven J.M. Jones
Canada’s Michael Smith Genome Sciences Centre at BC Cancer, Vancouver, British Columbia, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada; Department of Molecular Biology and Biochemistry, Simon Fraser University, Vancouver, British Columbia, Canada
Isidro Cortes-Ciriano
European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, Cambridge, CB10 1SD, UK
Marco A. Marra
Canada’s Michael Smith Genome Sciences Centre at BC Cancer, Vancouver, British Columbia, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
Chad J. Creighton
Division of Biostatistics, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA; Department of Medicine, Baylor College of Medicine, Houston, TX, USA; Corresponding author
Summary: The global impact of somatic structural variants (SVs) on gene regulation in advanced tumors with complex treatment histories has been mostly uncharacterized. Here, using whole-genome and RNA sequencing from 570 recurrent or metastatic tumors, we report the altered expression of hundreds of genes in association with nearby SV breakpoints, including oncogenes and G-protein-coupled receptor-related genes such as PLEKHG2. A significant fraction of genes with SV-expression associations correlate with worse patient survival in primary and advanced cancers, including SRD5A1. In many instances, SV-expression associations involve retrotransposons being translocated near genes. High overall SV burden is associated with treatment with DNA alkylating agents or taxanes and altered expression of metabolism-associated genes. SV-expression associations within tumors from topoisomerase I inhibitor-treated patients include chromatin-related genes. Within anthracycline-treated tumors, SV breakpoints near chromosome 1p genes include PDE4B. Patient treatment and history can help understand the widespread SV-mediated cis-regulatory alterations found in cancer.
