The topography of mutational processes in breast cancer genomes
Somatic mutations in human cancers show unevenness in genomic distribution that correlate with aspects of genome structure and function. These mutations are, however, generated by multiple mutational processes operating through the cellular lineage between the fertilized egg and the cancer cell, each composed of specific DNA damage and repair components and leaving its own characteristic mutational signature on the genome. Using somatic mutation catalogues from 560 breast cancer whole-genome sequences, here we show that each of 12 base substitution, 2 insertion/deletion (indel) and 6 rearrangement mutational signatures present in breast tissue, exhibit distinct relationships with genomic features relating to transcription, DNA replication and chromatin organization. This signature-based approach permits visualization of the genomic distribution of mutational processes associated with APOBEC enzymes, mismatch repair deficiency and homologous recombinational repair deficiency, as well as mutational processes of unknown aetiology. Furthermore, it highlights mechanistic insights including a putative replication-dependent mechanism of APOBEC-related mutagenesis.
|Persistent URL||dx.doi.org/10.1038/ncomms11383, hdl.handle.net/1765/90981|
|Grant||This work was funded by the European Commission 7th Framework Programme; grant id fp7/601876 - Testing and validation of bispecific antibody combinations targeting treatment-resistant cancer stem cells using organoid-based screening tools: a new drug discovery paradigm (SUPPRESSTEM), This work was funded by the European Commission 7th Framework Programme; grant id fp7/259893 - The DNA damage response and breast cancer (DDRESPONSE)|
Morganella, S, Alexandrov, L.B, Glodzik, D, Zou, X, Davies, H, Staaf, J, … Nik-Zainal, S. (2016). The topography of mutational processes in breast cancer genomes. Nature Communications, 7. doi:10.1038/ncomms11383