Topography of mutational signatures in human cancer
Burçak Otlu,
Marcos Díaz-Gay,
Ian Vermes,
Erik N. Bergstrom,
Maria Zhivagui,
Mark Barnes,
Ludmil B. Alexandrov
Affiliations
Burçak Otlu
Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, CA 92093, USA; Department of Bioengineering, UC San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, UC San Diego, La Jolla, CA 92037, USA; Department of Health Informatics, Graduate School of Informatics, Middle East Technical University, Ankara 06800, Turkey
Marcos Díaz-Gay
Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, CA 92093, USA; Department of Bioengineering, UC San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, UC San Diego, La Jolla, CA 92037, USA
Ian Vermes
COSMIC, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK
Erik N. Bergstrom
Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, CA 92093, USA; Department of Bioengineering, UC San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, UC San Diego, La Jolla, CA 92037, USA
Maria Zhivagui
Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, CA 92093, USA; Department of Bioengineering, UC San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, UC San Diego, La Jolla, CA 92037, USA
Mark Barnes
Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, CA 92093, USA; Department of Bioengineering, UC San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, UC San Diego, La Jolla, CA 92037, USA
Ludmil B. Alexandrov
Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, CA 92093, USA; Department of Bioengineering, UC San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, UC San Diego, La Jolla, CA 92037, USA; Corresponding author
Summary: The somatic mutations found in a cancer genome are imprinted by different mutational processes. Each process exhibits a characteristic mutational signature, which can be affected by the genome architecture. However, the interplay between mutational signatures and topographical genomic features has not been extensively explored. Here, we integrate mutations from 5,120 whole-genome-sequenced tumors from 40 cancer types with 516 topographical features from ENCODE to evaluate the effect of nucleosome occupancy, histone modifications, CTCF binding, replication timing, and transcription/replication strand asymmetries on the cancer-specific accumulation of mutations from distinct mutagenic processes. Most mutational signatures are affected by topographical features, with signatures of related etiologies being similarly affected. Certain signatures exhibit periodic behaviors or cancer-type-specific enrichments/depletions near topographical features, revealing further information about the processes that imprinted them. Our findings, disseminated via the COSMIC (Catalog of Somatic Mutations in Cancer) signatures database, provide a comprehensive online resource for exploring the interactions between mutational signatures and topographical features across human cancer.
