A Sticky Multinomial Mixture Model of Strand-Coordinated Mutational Processes in Cancer

  • Itay Sason
  • Damian Wojtowicz
  • Welles Robinson
  • Mark D. M. Leiserson
  • Teresa M. Przytycka
  • Roded SharanEmail author
Conference paper
Part of the Lecture Notes in Computer Science book series (LNCS, volume 11467)


The characterization of mutational processes in terms of their signatures of activity relies, to the most part, on the assumption that mutations in a given cancer genome are independent of one another. Recently, it was discovered that certain segments of mutations, termed processive groups, occur on the same DNA strand and are generated by a single process or signature. Here we provide a first probabilistic model of mutational signatures that accounts for their observed stickiness and strand-coordination. The model conditions on the observed strand for each mutation, and allows the same signature to generate a run of mutations. We show that this model provides a more accurate description of the properties of mutagenic processes than independent-mutation models or strand oblivous models, achieving substantially higher likelihood on held-out data. We apply this model to characterize the processivity of mutagenic processes across multiple types of cancer in terms of replication and transcriptional strand-coordination.



This study was supported in part by a fellowship from the Edmond J. Safra Center for Bioinformatics at Tel-Aviv University. DW and TMP are supported by the Intramural Research Programs of the National Library of Medicine (NLM), National Institutes of Health, USA. RS was supported by Len Blavatnik and the Blavatnik Family foundation. We thank Mark Keller for his help in processing mutation datasets.


  1. 1.
    Alexandrov, L.B., Nik-Zainal, S., Wedge, D.C., Aparicio, S., Behjati, S., et al.: Signatures of mutational processes in human cancer. Nature 500(7463), 415–421 (2013)CrossRefGoogle Scholar
  2. 2.
    Alexandrov, L.B., Nik-Zainal, S., Wedge, D.C., Campbell, P.J., Stratton, M.R.: Deciphering signatures of mutational processes operative in human cancer. Cell Rep. 3(1), 246–259 (2013)CrossRefGoogle Scholar
  3. 3.
    Davies, H., Glodzik, D., Morganella, S., Yates, L.R., Staaf, J., et al.: HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat. Med. 23(4), 517–525 (2017)CrossRefGoogle Scholar
  4. 4.
    Davies, H., Morganella, S., Purdie, C.A., Jang, S., Borgen, E., et al.: Whole-genome sequencing reveals breast cancers with mismatch repair deficiency. Cancer Res. 77(18), 4755–4762 (2017)Google Scholar
  5. 5.
    Fischer, A., Illingworth, C.J., Campbell, P.J., Mustonen, V.: EMu: probabilistic inference of mutational processes and their localization in the cancer genome. Genome Biol. 14(4), 1–10 (2013)CrossRefGoogle Scholar
  6. 6.
    Forbes, S.A., Beare, D., Boutselakis, H., Bamford, S., Bindal, N., et al.: Cosmic: somatic cancer genetics at high-resolution. Nucleic Acids Res. 45(D1), D777–D783 (2017)CrossRefGoogle Scholar
  7. 7.
    Funnell, T., Zhang, A., Shiah, Y.-J., Grewal, D., Lesurf, R., et al.: Integrated single-nucleotide and structural variation signatures of DNA-repair deficient human cancers. bioRxiv, p. 267500 (2018)Google Scholar
  8. 8.
    Haradhvala, N., Polak, P., Stojanov, P., Covington, K., Shinbrot, E., et al.: Mutational strand asymmetries in cancer genomes reveal mechanisms of DNA damage and repair. Cell 164(3), 538–549 (2016)CrossRefGoogle Scholar
  9. 9.
    Helleday, T., Eshtad, S., Nik-Zainal, S.: Mechanisms underlying mutational signatures in human cancers. Nat. Rev. Genet. 15(9), 585–598 (2014)CrossRefGoogle Scholar
  10. 10.
    Huvet, M., Nicolay, S., Touchon, M., Audit, B., d’Aubenton Carafa, Y., Alain Arneodo, C.T.: Human gene organization driven by the coordination of replication and transcription. Genome Res. 17(9), 1278–1285 (2007)Google Scholar
  11. 11.
    Kim, J., Mouw, K.W., Polak, P., Braunstein, L.Z., Kamburov, A., et al.: Somatic ERCC2 mutations are associated with a distinct genomic signature in urothelial tumors. Nat. Genet. 48(6), 600–606 (2016)CrossRefGoogle Scholar
  12. 12.
    Morganella, S., Alexandrov, L.B., Glodzik, D., Zou, X., Davies, H., et al.: The topography of mutational processes in breast cancer genomes. Nat. Commun. 7, 11383 (2016)Google Scholar
  13. 13.
    Nik-Zainal, S., Davies, H., Staaf, J., Ramakrishna, M., Glodzik, D., et al.: Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature 534(7605), 47–54 (2016)CrossRefGoogle Scholar
  14. 14.
    Nik-Zainal, S., Wedge, D.C., Alexandrov, L.B., Petljak, M., Butler, A.P., et al.: Association of a germline copy number polymorphism of APOBEC3A and APOBEC3B with burden of putative APOBEC-dependent mutations in breast cancer. Nat. Genet. 46(5), 487–491 (2014)CrossRefGoogle Scholar
  15. 15.
    Polak, P., Kim, J., Braunstein, L.Z., Karlic, R., Haradhavala, N.J., et al.: A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer. Nat. Genet. 49(10), 1476 (2017)Google Scholar
  16. 16.
    Refsland, E., Harris, R.: The APOBEC3 family of retroelement restriction factors. Curr. Top. Microbiol. Immunol. 371, 1–27 (2013)Google Scholar
  17. 17.
    Rosales, R.A., Drummond, R.D., Valieris, R., Dias-Neto, E., da Silva, I.T.: signeR: an empirical Bayesian approach to mutational signature discovery. Bioinformatics 33(1), 8–16 (2016)CrossRefGoogle Scholar
  18. 18.
    Seplyarskiy, V., Soldatov, R., Popadin, K., Antonarakis, S., Bazykin, G., Nikolaev, S.: APOBEC-induced mutations in human cancers are strongly enriched on the lagging DNA strand during replication. Genome Res. 26, 174–82 (2016)CrossRefGoogle Scholar
  19. 19.
    Shiraishi, Y., Tremmel, G., Miyano, S., Stephens, M.: A simple model-based approach to inferring and visualizing cancer mutation signatures. PLOS Genet. 11(12), e1005657 (2015)Google Scholar
  20. 20.
    Srivatsan, A., Tehranchi, A., MacAlpine, D.M., Wang, J.D.: Co-orientation of replication and transcription preserves genome integrity. PLoS Genet. 6(1), e1000810 (2010)Google Scholar
  21. 21.
    Supek, F., Lehner, B.: Clustered mutation signatures reveal that error-prone DNA repair targets mutations to active genes. Cell 170(3), 534–547.e23 (2017)Google Scholar
  22. 22.
    Tomkova, M., Tomek, J., Kriaucionis, S., Schuster-Böckler, B.: Mutational signature distribution varies with DNA replication timing and strand asymmetry. Genome Biol. 19(1), 129 (2018)Google Scholar
  23. 23.
    Tubbs, A., Nussenzweig, A.: Endogenous DNA damage as a source of genomic instability in cancer. Cell 168(4), 644–656 (2017)CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Itay Sason
    • 1
  • Damian Wojtowicz
    • 2
  • Welles Robinson
    • 3
  • Mark D. M. Leiserson
    • 3
  • Teresa M. Przytycka
    • 2
  • Roded Sharan
    • 1
    Email author
  1. 1.School of Computer ScienceTel Aviv UniversityTel AvivIsrael
  2. 2.National Center for Biotechnology Information, National Library of MedicineNational Institutes of HealthBethesdaUSA
  3. 3.Center for Bioinformatics and Computational BiologyUniversity of MarylandCollege ParkUSA

Personalised recommendations