Abstract
Whole-genome sequencing has brought the cancer genomics community into new territory. Thanks to the sheer power provided by the thousands of mutations present in each patient’s cancer, we have been able to discern generic patterns of mutations, termed ‘mutational signatures’, that arise during tumorigenesis. These mutational signatures provide new insights into the causes of individual cancers, revealing both endogenous and exogenous factors that have influenced cancer development. This Review brings readers up to date in a field that is expanding in computational, experimental and clinical directions. We focus on recent conceptual advances, underscoring some of the caveats associated with using the mutational signature frameworks and highlighting the latest experimental insights. We conclude by bringing attention to areas that are likely to see advancements in clinical applications.
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References
Nik-Zainal, S. et al. Mutational processes molding the genomes of 21 breast cancers. Cell 149, 979–993 (2012). This study presents catalogues of somatic mutations from 21 breast cancers, the respective mutational signatures of which were extracted by mathematical methods.
Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013). This study reports 21 distinct mutational signatures extracted from several cancer types, which form the basis of COSMIC mutational signatures v2.
Alexandrov, L. B. et al. The repertoire of mutational signatures in human cancer. Nature 578, 94–101 (2020). This study reports the largest number of mutational signatures to date, which form the basis of COSMIC mutational signatures v3, and introduces DBSs and IDs.
Degasperi, A. et al. A practical framework and online tool for mutational signature analyses show inter-tissue variation and driver dependencies. Nat. Cancer 1, 249–263 (2020). This study introduces a practical framework and Signal, an online tool, to analyse mutational signatures. It also reports evidence of tissue-specific variability in mutational signatures, which may impact tumour classification and clinical application.
Li, Y. et al. Patterns of somatic structural variation in human cancer genomes. Nature 578, 112–121 (2020).
ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-cancer analysis of whole genomes. Nature 578, 82–93 (2020).
Alexandrov, L. B. et al. Clock-like mutational processes in human somatic cells. Nat. Genet. 47, 1402–1407 (2015).
Secrier, M. et al. Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance. Nat. Genet. 48, 1131–1141 (2016).
Pich, O. et al. The mutational footprints of cancer therapies. Nat. Genet. 51, 1732–1740 (2019).
Baez-Ortega, A. & Gori, K. Computational approaches for discovery of mutational signatures in cancer. Brief. Bioinforma. 20, 77–88 (2019).
Omichessan, H., Severi, G. & Perduca, V. Computational tools to detect signatures of mutational processes in DNA from tumours: a review and empirical comparison of performance. PLoS ONE 14, e0221235 (2019).
Koh, G., Zou, X. & Nik-Zainal, S. Mutational signatures: experimental design and analytical framework. Genome Biol. 21, 37 (2020).
Kucab, J. E. et al. A compendium of mutational signatures of environmental agents. Cell 177, 821–836.e16 (2019). This is the largest and most comprehensive screen of environmental mutagen-associated mutational signatures published to date.
Rosenthal, R., McGranahan, N., Herrero, J., Taylor, B. S. & Swanton, C. DeconstructSigs: delineating mutational processes in single tumors distinguishes DNA repair deficiencies and patterns of carcinoma evolution. Genome Biol. 17, 31 (2016).
Blokzijl, F., Janssen, R., van Boxtel, R. & Cuppen, E. MutationalPatterns: comprehensive genome-wide analysis of mutational processes. Genome Med. 10, 33 (2018).
Fantini, D., Vidimar, V., Yu, Y., Condello, S. & Meeks, J. J. MutSignatures: an R package for extraction and analysis of cancer mutational signatures. Sci. Rep. 10, 18217 (2020).
Cartolano, M. et al. CaMuS: simultaneous fitting and de novo imputation of cancer mutational signature. Sci. Rep. 10, 19316 (2020).
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, 246–259 (2013). This article describes the use of non-negative matrix factorization to extract mutational signatures.
Huang, X., Wojtowicz, D. & Przytycka, T. M. Detecting presence of mutational signatures in cancer with confidence. Bioinformatics 34, 330–337 (2018).
Petljak, M. et al. Characterizing mutational signatures in human cancer cell lines reveals episodic APOBEC mutagenesis. Cell 176, 1282–1294.e20 (2019).
Helleday, T., Eshtad, S. & Nik-Zainal, S. Mechanisms underlying mutational signatures in human cancers. Nat. Rev. Genet. 15, 585–598 (2014).
Davies, H. et al. Whole-genome sequencing reveals breast cancers with mismatch repair deficiency. Cancer Res. 77, 4755–4762 (2017).
Lee-Six, H. et al. The landscape of somatic mutation in normal colorectal epithelial cells. Nature 574, 532–537 (2019).
Nik-Zainal, S. et al. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature 534, 47–54 (2016). This study presents the first RSs and introduces a framework to classify these.
Letouze, E. et al. Mutational signatures reveal the dynamic interplay of risk factors and cellular processes during liver tumorigenesis. Nat. Commun. 8, 1315 (2017).
Hillman, R. T., Chisholm, G. B., Lu, K. H. & Futreal, P. A. Genomic rearrangement signatures and clinical outcomes in high-grade serous ovarian cancer. J. Natl Cancer Inst. 110, 265–272 (2018).
Kamp, J. A., van Schendel, R., Dilweg, I. W. & Tijsterman, M. BRCA1-associated structural variations are a consequence of polymerase theta-mediated end-joining. Nat. Commun. 11, 3615 (2020).
Mateos-Gomez, P. A. et al. Mammalian polymerase theta promotes alternative NHEJ and suppresses recombination. Nature 518, 254–257 (2015).
Ceccaldi, R. et al. Homologous-recombination-deficient tumours are dependent on Poltheta-mediated repair. Nature 518, 258–262 (2015).
Bayard, Q. et al. Cyclin A2/E1 activation defines a hepatocellular carcinoma subclass with a rearrangement signature of replication stress. Nat. Commun. 9, 5235 (2018).
Macintyre, G. et al. Copy number signatures and mutational processes in ovarian carcinoma. Nat. Genet. 50, 1262–1270 (2018).
Wang, S. et al. Copy number signature analysis tool and its application in prostate cancer reveals distinct mutational processes and clinical outcomes. PLoS Genet. 17, e1009557 (2021).
Steele, C. D. et al. Undifferentiated sarcomas develop through distinct evolutionary pathways. Cancer Cell 35, 441–456 (2019).
Morganella, S. et al. The topography of mutational processes in breast cancer genomes. Nat. Commun. 7, 11383 (2016).
Lindahl, T. An N-glycosidase from Escherichia coli that releases free uracil from DNA containing deaminated cytosine residues. Proc. Natl Acad. Sci. USA 71, 3649–3653 (1974).
Krokan, H. E. & Bjoras, M. Base excision repair. Cold Spring Harb. Perspect. Biol. 5, a012583 (2013).
Strauss, B. S. The “A” rule revisited: polymerases as determinants of mutational specificity. DNA Repair 1, 125–135 (2002).
Maura, F. et al. A practical guide for mutational signature analysis in hematological malignancies. Nat. Commun. 10, 2969 (2019).
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, 8–16 (2017).
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, R39 (2013).
Kasar, S. et al. Whole-genome sequencing reveals activation-induced cytidine deaminase signatures during indolent chronic lymphocytic leukaemia evolution. Nat. Commun. 6, 8866 (2015).
Kim, J. et al. Somatic ERCC2 mutations are associated with a distinct genomic signature in urothelial tumors. Nat. Genet. 48, 600–606 (2016).
Campbell, B. B. et al. Comprehensive analysis of hypermutation in human cancer. Cell 171, 1042–1056.e10 (2017).
Shen, J. C., Rideout, W. M. 3rd & Jones, P. A. High frequency mutagenesis by a DNA methyltransferase. Cell 71, 1073–1080 (1992).
Pfeifer, G. P. Mutagenesis at methylated CpG sequences. Curr. Top. Microbiol. 301, 259–281 (2006).
Blokzijl, F. et al. Tissue-specific mutation accumulation in human adult stem cells during life. Nature 538, 260–264 (2016).
Lugli, N. et al. Enhanced rate of acquisition of point mutations in mouse intestinal adenomas compared to normal tissue. Cell Rep. 19, 2185–2192 (2017).
Dulak, A. M. et al. Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity. Nat. Genet. 45, 478–486 (2013).
Angus, L. et al. The genomic landscape of metastatic breast cancer highlights changes in mutation and signature frequencies. Nat. Genet. 51, 1450–1458 (2019).
De Mattos-Arruda, L. et al. The genomic and immune landscapes of lethal metastatic breast cancer. Cell Rep. 27, 2690–2708.e10 (2019).
Priestley, P. et al. Pan-cancer whole-genome analyses of metastatic solid tumours. Nature 575, 210–216 (2019).
Christensen, S. et al. 5-Fluorouracil treatment induces characteristic T>G mutations in human cancer. Nat. Commun. 10, 4571 (2019).
Tomkova, M. et al. Deciphering the causes of the COSMIC mutational signature 17 by combining pan-cancer data with experimental mouse models [abstract]. Cancer Res. 79, 4661 (2019).
Nik-Zainal, S. et al. The genome as a record of environmental exposure. Mutagenesis 30, 763–770 (2015).
Dvorak, K. et al. Bile acids in combination with low pH induce oxidative stress and oxidative DNA damage: relevance to the pathogenesis of Barrett’s oesophagus. Gut 56, 763–771 (2007).
Inoue, M. et al. Induction of chromosomal gene mutations in Escherichia coli by direct incorporation of oxidatively damaged nucleotides. New evaluation method for mutagenesis by damaged DNA precursors in vivo. J. Biol. Chem. 273, 11069–11074 (1998).
Viel, A. et al. A specific mutational signature associated with DNA 8-oxoguanine persistence in MUTYH-defective colorectal cancer. EBioMedicine 20, 39–49 (2017).
Pilati, C. et al. Mutational signature analysis identifies MUTYH deficiency in colorectal cancers and adrenocortical carcinomas. J. Pathol. 242, 10–15 (2017).
Zou, X. Q. et al. A systematic CRISPR screen defines mutational mechanisms underpinning signatures caused by replication errors and endogenous DNA damage. Nat. Cancer 2, 643–657 (2021).
Kuijk, E. et al. The mutational impact of culturing human pluripotent and adult stem cells. Nat. Commun. 11, 2493 (2020).
Rouhani, F. J. et al. Mutational history of a human cell lineage from somatic to induced pluripotent stem cells. PLoS Genet. 12, e1005932 (2016).
Martincorena, I. et al. Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880–886 (2015).
Martincorena, I. et al. Somatic mutant clones colonize the human esophagus with age. Science 362, 911–917 (2018).
Brunner, S. F. et al. Somatic mutations and clonal dynamics in healthy and cirrhotic human liver. Nature 574, 538–542 (2019).
Moore, L. et al. The mutational landscape of normal human endometrial epithelium. Nature 580, 640–646 (2020).
Lawson, A. R. J. et al. Extensive heterogeneity in somatic mutation and selection in the human bladder. Science 370, 75–82 (2020).
Yoshida, K. et al. Tobacco smoking and somatic mutations in human bronchial epithelium. Nature 578, 266–272 (2020).
D’Antonio, M. et al. Insights into the mutational burden of human induced pluripotent stem cells from an integrative multi-omics approach. Cell Rep. 24, 883–894 (2018).
Rouhani, F. J. et al. Substantial somatic genomic variation and selection for BCOR mutations in human induced pluripotent stem cells. Preprint at bioRxiv https://doi.org/10.1101/2021.02.04.429731 (2021).
Nik-Zainal, S. & Hall, B. A. Cellular survival over genomic perfection. Science 366, 802–803 (2019).
Yates, L. R. et al. Genomic evolution of breast cancer metastasis and relapse. Cancer Cell 32, 169–184.e7 (2017).
Naxerova, K. et al. Origins of lymphatic and distant metastases in human colorectal cancer. Science 357, 55–60 (2017).
Robinson, D. R. et al. Integrative clinical genomics of metastatic cancer. Nature 548, 297–303 (2017).
Yaeger, R. et al. Clinical sequencing defines the genomic landscape of metastatic colorectal cancer. Cancer Cell 33, 125–136.e3 (2018).
Liu, D. et al. Mutational patterns in chemotherapy resistant muscle-invasive bladder cancer. Nat. Commun. 8, 2193 (2017).
Swanton, C., McGranahan, N., Starrett, G. J. & Harris, R. S. APOBEC enzymes: mutagenic fuel for cancer evolution and heterogeneity. Cancer Discov. 5, 704–712 (2015).
Lefebvre, C. et al. Mutational profile of metastatic breast cancers: a retrospective analysis. PLoS Med. 13, e1002201 (2016).
Pleasance, E. et al. Pan-cancer analysis of advanced patient tumors reveals interactions between therapy and genomic landscapes. Nat. Cancer 1, 452–468 (2020).
Mendelaar, P. A. J. et al. Whole genome sequencing of metastatic colorectal cancer reveals prior treatment effects and specific metastasis features. Nat. Commun. 12, 574 (2021).
Rubanova, Y. et al. Reconstructing evolutionary trajectories of mutation signature activities in cancer using TrackSig. Nat. Commun. 11, 731 (2020).
Riva, L. et al. The mutational signature profile of known and suspected human carcinogens in mice. Nat. Genet. 52, 1189–1197 (2020).
Olivier, M. et al. Modelling mutational landscapes of human cancers in vitro. Sci. Rep. 4, 4482 (2014).
Besaratinia, A. & Pfeifer, G. P. Applications of the human p53 knock-in (Hupki) mouse model for human carcinogen testing. FASEB J. 24, 2612–2619 (2010).
Liu, Z. et al. Human tumor p53 mutations are selected for in mouse embryonic fibroblasts harboring a humanized p53 gene. Proc. Natl Acad. Sci. USA 101, 2963–2968 (2004).
Szikriszt, B. et al. A comprehensive survey of the mutagenic impact of common cancer cytotoxics. Genome Biol. 17, 99 (2016).
Meier, B. et al. C. elegans whole-genome sequencing reveals mutational signatures related to carcinogens and DNA repair deficiency. Genome Res. 24, 1624–1636 (2014).
Volkova, N. V. et al. Mutational signatures are jointly shaped by DNA damage and repair. Nat. Commun. 11, 2169 (2020).
Boot, A. et al. In-depth characterization of the cisplatin mutational signature in human cell lines and in esophageal and liver tumors. Genome Res. 28, 654–665 (2018).
Pleguezuelos-Manzano, C. et al. Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli. Nature 580, 269–273 (2020).
Dziubanska-Kusibab, P. J. et al. Colibactin DNA-damage signature indicates mutational impact in colorectal cancer. Nat. Med. 26, 1063–1069 (2020).
Boot, A. et al. Characterization of colibactin-associated mutational signature in an Asian oral squamous cell carcinoma and in other mucosal tumor types. Genome Res. 30, 803–813 (2020).
Zou, X. et al. Validating the concept of mutational signatures with isogenic cell models. Nat. Commun. 9, 1744 (2018).
Jager, M. et al. Deficiency of nucleotide excision repair is associated with mutational signature observed in cancer. Genome Res. 29, 1067–1077 (2019).
Drost, J. et al. Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer. Science 358, 234–238 (2017).
Martincorena, I. & Campbell, P. J. Somatic mutation in cancer and normal cells. Science 349, 1483–1489 (2015).
Bryant, H. E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005).
Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).
Fong, P. C. et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123–134 (2009).
Telli, M. L. et al. Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer. Clin. Cancer Res. 22, 3764–3773 (2016).
Abkevich, V. et al. Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. Br. J. Cancer 107, 1776–1782 (2012).
Birkbak, N. J. et al. Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents. Cancer Discov. 2, 366–375 (2012).
Popova, T. et al. Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. Cancer Res. 72, 5454–5462 (2012).
Timms, K. M. et al. Association of BRCA1/2 defects with genomic scores predictive of DNA damage repair deficiency among breast cancer subtypes. Breast Cancer Res. 16, 475–483 (2014).
Davies, H. et al. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat. Med. 23, 517–525 (2017). This study describes the first clinical predictive tool, HRDetect, designed using a panel of mutational signatures to predict HRD.
Zhao, E. Y. et al. Homologous recombination deficiency and platinum-based therapy outcomes in advanced breast cancer. Clin. Cancer Res. 23, 7521–7530 (2017).
Nones, K. et al. Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers. Ann. Oncol. 30, 1071–1079 (2019).
Nguyen, L., Martens, J. W. M., Van Hoeck, A. & Cuppen, E. Pan-cancer landscape of homologous recombination deficiency. Nat. Commun. 11, 5584 (2020).
Gulhan, D. C., Lee, J. J., Melloni, G. E. M., Cortes-Ciriano, I. & Park, P. J. Detecting the mutational signature of homologous recombination deficiency in clinical samples. Nat. Genet. 51, 912–919 (2019).
Staaf, J. et al. Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study. Nat. Med. 25, 1526–1533 (2019).
Chopra, N. et al. Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer. Nat. Commun. 11, 2662 (2020).
Thibodeau, S. N., Bren, G. & Schaid, D. Microsatellite instability in cancer of the proximal colon. Science 260, 816–819 (1993).
Ionov, Y., Peinado, M. A., Malkhosyan, S., Shibata, D. & Perucho, M. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363, 558–561 (1993).
Kim, T. M., Laird, P. W. & Park, P. J. The landscape of microsatellite instability in colorectal and endometrial cancer genomes. Cell 155, 858–868 (2013).
Lynch, H. T., Snyder, C. L., Shaw, T. G., Heinen, C. D. & Hitchins, M. P. Milestones of Lynch syndrome: 1895–2015. Nat. Rev. Cancer 15, 181–194 (2015).
Le, D. T. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409–413 (2017).
Mandal, R. et al. Genetic diversity of tumors with mismatch repair deficiency influences anti-PD-1 immunotherapy response. Science 364, 485–491 (2019).
Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).
Middha, S. et al. Reliable pan-cancer microsatellite instability assessment by using targeted next-generation sequencing data. JCO Precis. Oncol. 1, 1–17 (2017).
Niu, B. F. et al. MSIsensor: microsatellite instability detection using paired tumor-normal sequence data. Bioinformatics 30, 1015–1016 (2014).
Salipante, S. J., Scroggins, S. M., Hampel, H. L., Turner, E. H. & Pritchard, C. C. Microsatellite instability detection by next generation sequencing. Clin. Chem. 60, 1192–1199 (2014).
Germano, G. et al. Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth. Nature 552, 116–120 (2017).
Lemery, S., Keegan, P. & Pazdur, R. First FDA approval agnostic of cancer site — when a biomarker defines the indication. N. Engl. J. Med. 377, 1409–1412 (2017).
Stelloo, E. et al. Practical guidance for mismatch repair-deficiency testing in endometrial cancer. Ann. Oncol. 28, 96–102 (2017).
Kawakami, H., Zaanan, A. & Sinicrope, F. A. Microsatellite instability testing and its role in the management of colorectal cancer. Curr. Treat. Options Oncol. 16, 30 (2015).
Buhard, O. et al. Multipopulation analysis of polymorphisms in five mononucleotide repeats used to determine the microsatellite instability status of human tumors. J. Clin. Oncol. 24, 241–251 (2006).
Huang, M. N. et al. MSIseq: software for assessing microsatellite instability from catalogs of somatic mutations. Sci. Rep. 5, 13321 (2015).
Fabrizio, D. A. et al. Beyond microsatellite testing: assessment of tumor mutational burden identifies subsets of colorectal cancer who may respond to immune checkpoint inhibition. J. Gastrointest. Oncol. 9, 610–617 (2018).
Schrock, A. B. et al. Tumor mutational burden is predictive of response to immune checkpoint inhibitors in MSI-high metastatic colorectal cancer. Ann. Oncol. 30, 1096–1103 (2019).
Mehnert, J. M. et al. Immune activation and response to pembrolizumab in POLE-mutant endometrial cancer. J. Clin. Invest. 126, 2334–2340 (2016).
Howitt, B. E. et al. Association of polymerase e-mutated and microsatellite-instable endometrial cancers with neoantigen load, number of tumor-infiltrating lymphocytes, and expression of PD-1 and PD-L1. JAMA Oncol. 1, 1319–1323 (2015).
Johanns, T. M. et al. Immunogenomics of hypermutated glioblastoma: a patient with germline POLE deficiency treated with checkpoint blockade immunotherapy. Cancer Discov. 6, 1230–1236 (2016).
Momen, S. et al. Dramatic response of metastatic cutaneous angiosarcoma to an immune checkpoint inhibitor in a patient with xeroderma pigmentosum: whole-genome sequencing aids treatment decision in end-stage disease. Cold Spring Harb. Mol. Case Stud. 5, a004408 (2019).
Chung, J. et al. DNA polymerase and mismatch repair exert distinct microsatellite instability signatures in normal and malignant human cells. Cancer Discov. 11, 1176–1191 (2020).
Roberts, S. A. et al. An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers. Nat. Genet. 45, 970–976 (2013).
Nik-Zainal, S. 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, 487–491 (2014).
Starrett, G. J. et al. The DNA cytosine deaminase APOBEC3H haplotype I likely contributes to breast and lung cancer mutagenesis. Nat. Commun. 7, 12918 (2016).
Middlebrooks, C. D. et al. Association of germline variants in the APOBEC3 region with cancer risk and enrichment with APOBEC-signature mutations in tumors. Nat. Genet. 48, 1330–1338 (2016).
Yokoyama, A. et al. Age-related remodelling of oesophageal epithelia by mutated cancer drivers. Nature 565, 312–317 (2019).
Walker, B. A. et al. APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma. Nat. Commun. 6, 6997 (2015).
Wang, S. X., Jia, M. M., He, Z. K. & Liu, X. S. APOBEC3B and APOBEC mutational signature as potential predictive markers for immunotherapy response in non-small cell lung cancer. Oncogene 37, 3924–3936 (2018).
Boichard, A., Tsigelny, I. F. & Kurzrock, R. High expression of PD-1 ligands is associated with kataegis mutational signature and APOBEC3 alterations. Oncoimmunology 6, e1284719 (2017).
Gibney, G. T., Weiner, L. M. & Atkins, M. B. Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol. 17, e542–e551 (2016).
Law, E. K. et al. The DNA cytosine deaminase APOBEC3B promotes tamoxifen resistance in ER-positive breast cancer. Sci. Adv. 2, e1601737 (2016).
Menghi, F. et al. The tandem duplicator phenotype as a distinct genomic configuration in cancer. Proc. Natl Acad. Sci. USA 113, E2373–E2382 (2016).
Menghi, F. et al. The tandem duplicator phenotype is a prevalent genome-wide cancer configuration driven by distinct gene mutations. Cancer Cell 34, 197–210.e5 (2018).
Willis, N. A. et al. Mechanism of tandem duplication formation in BRCA1-mutant cells. Nature 551, 590–595 (2017).
Popova, T. et al. Ovarian cancers harboring inactivating mutations in CDK12 display a distinct genomic instability pattern characterized by large tandem duplications. Cancer Res. 76, 1882–1891 (2016).
Macheret, M. & Halazonetis, T. D. Intragenic origins due to short G1 phases underlie oncogene-induced DNA replication stress. Nature 555, 112–116 (2018).
Glodzik, D. et al. A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers. Nat. Genet. 49, 341–348 (2017).
Quigley, D. A. et al. Genomic hallmarks and structural variation in metastatic prostate cancer. Cell 174, 758–769.e9 (2018).
Stephens, P. J. et al. The landscape of cancer genes and mutational processes in breast cancer. Nature 486, 400–404 (2012).
Schimmel, J., Kool, H., van Schendel, R. & Tijsterman, M. Mutational signatures of non-homologous and polymerase theta-mediated end-joining in embryonic stem cells. EMBO J. 36, 3634–3649 (2017).
Wyatt, D. W. et al. Essential roles for polymerase theta-mediated end joining in the repair of chromosome breaks. Mol. Cell 63, 662–673 (2016).
Higgins, G. S. et al. A small interfering RNA screen of genes involved in DNA repair identifies tumor-specific radiosensitization by POLQ knockdown. Cancer Res. 70, 2984–2993 (2010).
Yousefzadeh, M. J. et al. Mechanism of suppression of chromosomal instability by DNA polymerase POLQ. PLoS Genet. 10, e1004654 (2014).
Wang, Z. et al. DNA polymerase (POLQ) is important for repair of DNA double-strand breaks caused by fork collapse. J. Biol. Chem. 294, 3909–3919 (2019).
Wang, Y. K. et al. Genomic consequences of aberrant DNA repair mechanisms stratify ovarian cancer histotypes. Nat. Genet. 49, 856–865 (2017).
Maciejowski, J., Li, Y., Bosco, N., Campbell, P. J. & de Lange, T. Chromothripsis and kataegis induced by telomere crisis. Cell 163, 1641–1654 (2015).
Stephens, P. J. et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144, 27–40 (2011).
Umbreit, N. T. et al. Mechanisms generating cancer genome complexity from a single cell division error. Science 368, 282–294 (2020).
Shoshani, O. et al. Chromothripsis drives the evolution of gene amplification in cancer. Nature 591, 137–141 (2021).
Dagogo-Jack, I. & Shaw, A. T. Tumour heterogeneity and resistance to cancer therapies. Nat. Rev. Clin. Oncol. 15, 81–94 (2018).
Driscoll, C. B. et al. APOBEC3B-mediated corruption of the tumor cell immunopeptidome induces heteroclitic neoepitopes for cancer immunotherapy. Nat. Commun. 11, 790 (2020).
Roudko, V. et al. Shared immunogenic poly-epitope frameshift mutations in microsatellite unstable tumors. Cell 183, 1634–1649.e17 (2020).
Koster, J. & Plasterk, R. H. A. A library of neo open reading frame peptides (NOPs) as a sustainable resource of common neoantigens in up to 50% of cancer patients. Sci. Rep. 9, 6577 (2019).
Diaz, L. A. Jr & Bardelli, A. Liquid biopsies: genotyping circulating tumor DNA. J. Clin. Oncol. 32, 579–586 (2014).
Alix-Panabieres, C. & Pantel, K. Clinical applications of circulating tumor cells and circulating tumor dna as liquid biopsy. Cancer Discov. 6, 479–491 (2016).
Abbosh, C. et al. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature 545, 446–451 (2017).
Annala, M. et al. Circulating tumor DNA genomics correlate with resistance to abiraterone and enzalutamide in prostate cancer. Cancer Discov. 8, 444–457 (2018).
Dawson, S. J. et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N. Engl. J. Med. 368, 1199–1209 (2013).
Murtaza, M. et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 497, 108–112 (2013).
Misale, S. et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 486, 532–536 (2012).
Zviran, A. et al. Genome-wide cell-free DNA mutational integration enables ultra-sensitive cancer monitoring. Nat. Med. 26, 1114–1124 (2020).
Turnbull, C. et al. The 100 000 Genomes Project: bringing whole genome sequencing to the NHS. BMJ 361, k1687 (2018).
Weill Cornell Medicine. Weill Cornell Medicine, NewYork-Presbyterian Hospital, and Illumina collaborate on scalable clinical whole-genome sequencing initiative. EurekAlert https://www.eurekalert.org/pub_releases/2020-12/wcm-wcm120220.php (2020).
Haradhvala, N. J. et al. Mutational strand asymmetries in cancer genomes reveal mechanisms of DNA damage and repair. Cell 164, 538–549 (2016).
Acknowledgements
This work was funded by the Cancer Research UK (CRUK) Advanced Clinician Scientist Award (C60100/A23916), the Dr. Josef Steiner Cancer Research Award 2019, a Medical Research Council (MRC) Grant-in-Aid to the MRC Cancer Unit, the CRUK Pioneer Award, a Wellcome Strategic Award (WT101126), Basser Gray Prime Award 2020, and supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC-1215-20014).
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Contributions
S.N.-Z., G.K., A.D. and S.M. researched data for the article. S.N.-Z., G.K., A.D. and X.Z. contributed to discussion of content and writing the article. S.N.-Z., G.K. and X.Z. reviewed and edited the manuscript before submission.
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Competing interests
S.N.-Z. holds patents on clinical algorithms of mutational signatures and, during the completion of the manuscript, also had advisory roles for AstraZeneca, Artios Pharma Ltd and the Scottish Genome Project. The other authors declare no competing interests.
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Related links
Beyond 1 Million Genomes (B1MG): https://b1mg-project.eu
Signal: a Web-based tool for cancer and experimentally generated mutational signature exploration and analysis: https://signal.mutationalsignatures.com
Wellcome Trust Sanger Institute COSMIC signature resource: https://cancer.sanger.ac.uk/cosmic/signatures
Supplementary information
Glossary
- Homologous recombination deficiency
-
(HRD). An inability to repair DNA double-strand breaks via homologous recombination-based repair mechanisms, typically caused by germ line or somatic BRCA gene mutations.
- Poly(dA:dT)
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Homopolymeric stretches of deoxyadenosine (dA) or deoxythymidine (dT) nucleotides on one strand of double-stranded DNA. They are overabundant in eukaryotic genomes and constitute a hotspot of mutagenesis.
- Non-negative matrix factorization framework
-
An unsupervised machine learning framework in which a matrix is factorized into (usually) two matrices, with the property that all three matrices have no negative elements, thus allowing us to model a data matrix as linear combinations of a set of basis vectors (building blocks).
- Hierarchical Dirichlet process
-
A non-parametric Bayesian approach to clustering grouped data.
- Local n-jumps
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A cluster of n structural variants in a single genomic region, usually phased to a single derivative chromosome, exhibiting some copy number gains and junctions with inverted and non-inverted orientation.
- Chromoplexy
-
Large chained and weaved genomic rearrangements that involves multiple chromosomes.
- Template switching
-
A recombination-based mechanism in which stalled polymerase finds an alternative template such that it can ‘borrow’ to get around a DNA lesion on the damaged parent strand and restart replication. This is most commonly the newly synthesized daughter strand on the sister chromatid or other sequences with homology to the single-stranded DNA region.
- Matrix decomposition
-
Also called matrix factorization, works by decomposing the user-item interaction matrix into a product of two lower-dimensionality matrices, such as \(M\approx S\times E\), where M is the catalogue matrix, with mutation types as rows and samples as columns, S is the signature matrix, with mutation types as rows and signatures as columns, and E is the exposure matrix, with signatures as rows and samples as columns.
- Strauss’s A rule
-
The preferential incorporation of adenine opposite a non-instructional DNA blocking lesion or across an abasic site.
- Replication stress
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The slowing or stalling of replication fork progression and/or DNA synthesis in response to DNA damage or any hindrance to DNA replication.
- 8-Oxo-dGTP
-
8-Oxo-2′-deoxyguanosine 5′-triphosphate, the oxidized form of 2′-deoxyguanosine 5′-triphosphate (dGTP). It can mispair with A, leading to C>A/G>T transversion mutations.
- Synthetic lethality
-
Interaction between two genes when the perturbation of either gene alone is viable but the perturbation of either gene results in cell death.
- Microsatellite instability
-
(MSI). Variability in the length of base pair repeated sequences (less than 5 bp) due to short insertions/deletions caused by replication slippage and that is normally kept stable by mismatch repair.
- Kataegis
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A base substitution hypermutation that comprises C·G → T·A transitions and C·G → G·C transversions with a predilection for a thymine preceding the mutated cytosine (that is, a TpC context); it usually macroscopically colocalizes with structural variation.
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Koh, G., Degasperi, A., Zou, X. et al. Mutational signatures: emerging concepts, caveats and clinical applications. Nat Rev Cancer 21, 619–637 (2021). https://doi.org/10.1038/s41568-021-00377-7
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DOI: https://doi.org/10.1038/s41568-021-00377-7
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