RepairSig: Deconvolution of DNA damage and repaircontributions to the mutational landscape of cancer

Abstract

Many mutagenic processes leave characteristic imprints on cancer genomes known as mutational signatures. These signatures have been of recent interest regarding their applicability in studying processes shaping the mutational landscape of cancer. In particular, pinpointing the presence of altered DNA repair pathways can have important therapeutic implications. However, mutational signatures of DNA repair deficiencies are often hard to infer. This challenge emerges as a result of deficient DNA repair processes acting by modifying the outcome of other mutagens. Thus, they exhibit non-additive effects that are not depicted by the current paradigm for modeling mutational processes as independent signatures. To close this gap, we present RO_SCPLOWEPAIRC_SCPLOWSO_SCPLOWIGC_SCPLOW, a method that accounts for interactions between DNA damage and repair and is able to uncover unbiased signatures of deficient DNA repair processes. In particular, RO_SCPLOWEPAIRC_SCPLOWSO_SCPLOWIGC_SCPLOW was able to replace three MMR deficiency signatures previously proposed to be active in breast cancer, with just one signature strikingly similar to the experimentally derived signature. As the first method to model interactions between mutagenic processes, RO_SCPLOWEPAIRC_SCPLOWSO_SCPLOWIGC_SCPLOW is an important step towards biologically more realistic modeling of mutational processes in cancer. The source code for RO_SCPLOWEPAIRC_SCPLOWSO_SCPLOWIGC_SCPLOW is publicly available at https://github.com/ncbi/RepairSig.