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

doi:10.1016/j.celrep.2021.110023

Rearrangement-mediated cis-regulatory alterations in advanced patient tumors reveal interactions with therapy

Cell Rep. 2021 Nov 16;37(7):110023. doi: 10.1016/j.celrep.2021.110023.

Authors

Affiliations

¹ Division of Biostatistics, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
² Canada's Michael Smith Genome Sciences Centre at BC Cancer, Vancouver, British Columbia, Canada.
³ Department of Medical Oncology, BC Cancer, Vancouver, British Columbia, Canada.
⁴ 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.
⁵ European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, Cambridge, CB10 1SD, UK.
⁶ 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.
⁷ 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. Electronic address: creighto@bcm.edu.

Abstract

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.

Keywords: POG570; cancer; genomic rearrangement; metastasis; pan-cancer; recurrence; structural variants; structural variation; therapy; whole genome sequencing.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Chromosome Aberrations
DNA Copy Number Variations / genetics
Databases, Genetic
Exome Sequencing / methods
Gene Expression Regulation, Neoplastic / genetics*
Gene Rearrangement / genetics
Genome, Human
Genomic Structural Variation / genetics*
Genomics
Humans
Neoplasm Recurrence, Local / genetics*
Oncogenes
Sequence Analysis, RNA / methods
Translocation, Genetic / genetics
Whole Genome Sequencing / methods

Grants and funding

P30 CA125123/CA/NCI NIH HHS/United States