The topography of mutational processes in breast cancer genomes

Abstract

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.

APOBEC3A/B-induced mutagenesis is responsible for 20% of heritable mutations in the TpCpW context

“…2C). These observations are in line with the transcriptional asymmetry of APOBEC3A/B-induced mutations in bladder cancer and breast cancer (Nordentoft et al 2014;Morganella et al 2016) and likely reflect the accessibility of the nontranscribed strand to APOBEC3A/B, because the nontemplate strand is prone to single-strandedness (Skourti-Stathaki and Proudfoot 2014). The replication asymmetry of TpCpW→K mutations is observed both in transcribed and nontranscribed regions, implying that it is independent of the effect of transcription, although the extent of this asymmetry differs slightly between the template and the nontemplate strands because of contribution of chain-specific mutations ( Fig.…”

“…Mutations produced by APOBEC3A/B have known properties confirmed both in yeast and in human cancers: (1) They are C→D mutations in the TpCpN context (the more specific APOBEC3A/B signature is TpCpW→K, where D denotes A, T, or G; W denotes A or T; and K denotes G or T) (Burns et al 2013a;Taylor et al 2013;Chan et al 2015;Seplyarskiy et al 2016); (2) they often form strand-coordinated clusters (Nik-Zainal et al 2012;Roberts et al 2013;Taylor et al 2013); (3) they are strongly biased toward the lagging strand during replication (Haradhvala et al 2016;Hoopes et al 2016;Morganella et al 2016;Nik-Zainal et al 2016;Seplyarskiy et al 2016); (4) they are biased toward the nontranscribed strand, at least in breast and bladder cancer (Nordentoft et al 2014;Morganella et al 2016); and (5) cytosines deaminated to uracils by APOBEC frequently result in C→G substitutions. According to the current models, these mutations arise due to incomplete repair of U-G mismatches resulting in abasic sites.…”

Human mismatch repair system balances mutation rates between strands by removing more mismatches from the lagging strand

“…By using an approach that determines the replication fork polarity (FP) as the derivative of the replication timing (RT) (Baker et al 2012;Haradhvala et al 2016;Morganella et al 2016;Seplyarskiy et al 2016), we predicted for each genomic region whether the reference strand is replicated more frequently as leading (FP > 0) or lagging (FP < 0). Briefly, FP values reflect the ratio of the frequencies of passages of the replication fork in forward and reverse directions relative to the reference strain.…”

“…The strand asymmetry of mutations is also observed in MMRdeficient cancers (Haradhvala et al 2016;Morganella et al 2016). As MMR is primarily a coreplicative process (Hombauer et al 2011;Liao et al 2015), we hypothesized that this asymmetry is due to a joint effect of the differences in rates of mismatches produced by replicative polymerases on the leading and on the lagging strands, and differences in number of mutations repaired by the MMR between the two strands.…”

Elementary: breast cancer culprits leave their signatures on the double helix

“…13 Base substitution and rearrangement signatures increase in mutation density during time of replication, but at their own speed, whereas somatic deletions seem to be enriched later in replication. The level of asymmetry between strands varies between mutational signatures, with some signatures associated with the transcriptional strand, and some with the 'non-transcribed' strand.…”