Genomics & Informatics

  • 제19권4호
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  • Pages.40.1-40.11
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  • 2021
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  • 1598-866X(pISSN)
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  • 2234-0742(eISSN)
한국유전체학회 (Korea Genome Organization)
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Correlation-based and feature-driven mutation signature analyses to identify genetic features associated with DNA mutagenic processes in cancer genomes

  • Jeong, Hye Young (Department of Medical Informatics, College of Medicine, The Catholic University of Korea) ;
  • Yoo, Jinseon (Department of Medical Informatics, College of Medicine, The Catholic University of Korea) ;
  • Kim, Hyunwoo (Department of Medical Informatics, College of Medicine, The Catholic University of Korea) ;
  • Kim, Tae-Min (Department of Medical Informatics, College of Medicine, The Catholic University of Korea)
  • 투고 : 2021.08.19
  • 심사 : 2021.09.28
  • 발행 : 2021.12.31
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초록

Mutation signatures represent unique sequence footprints of somatic mutations resulting from specific DNA mutagenic and repair processes. However, their causal associations and the potential utility for genome research remain largely unknown. In this study, we performed PanCancer-scale correlative analyses to identify the genomic features associated with tumor mutation burdens (TMB) and individual mutation signatures. We observed that TMB was correlated with tumor purity, ploidy, and the level of aneuploidy, as well as with the expression of cell proliferation-related genes representing genomic covariates in evaluating TMB. Correlative analyses of mutation signature levels with genes belonging to specific DNA damage-repair processes revealed that deficiencies of NHEJ1 and ALKBH3 may contribute to mutations in the settings of APOBEC cytidine deaminase activation and DNA mismatch repair deficiency, respectively. We further employed a strategy to identify feature-driven, de novo mutation signatures and demonstrated that mutation signatures can be reconstructed using known causal features. Using the strategy, we further identified tumor hypoxia-related mutation signatures similar to the APOBEC-related mutation signatures, suggesting that APOBEC activity mediates hypoxia-related mutational consequences in cancer genomes. Our study advances the mechanistic insights into the TMB and signature-based DNA mutagenic and repair processes in cancer genomes. We also propose that feature-driven mutation signature analysis can further extend the categories of cancer-relevant mutation signatures and their causal relationships.

키워드

과제정보

This work was supported by the Korea Health Technology R&D Project via the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare (HI15C3224) and by National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (2019R1A2C2002315).

참고문헌

  1. Meyerson M, Gabriel S, Getz G. Advances in understanding cancer genomes through second-generation sequencing. Nat Rev Genet 2010;11:685-696. https://doi.org/10.1038/nrg2841
  2. Bozic I, Antal T, Ohtsuki H, Carter H, Kim D, Chen S, et al. Accumulation of driver and passenger mutations during tumor progression. Proc Natl Acad Sci U S A 2010;107:18545-18550. https://doi.org/10.1073/pnas.1010978107
  3. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646-674. https://doi.org/10.1016/j.cell.2011.02.013
  4. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372:2509-2520. https://doi.org/10.1056/NEJMoa1500596
  5. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology: mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015;348:124-128. https://doi.org/10.1126/science.aaa1348
  6. Samstein RM, Lee CH, Shoushtari AN, Hellmann MD, Shen R, Janjigian YY, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet 2019;51:202-206. https://doi.org/10.1038/s41588-018-0312-8
  7. Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 2013;499:214-218. https://doi.org/10.1038/nature12213
  8. Roberts SA, Gordenin DA. Hypermutation in human cancer genomes: footprints and mechanisms. Nat Rev Cancer 2014;14:786-800. https://doi.org/10.1038/nrc3816
  9. Helleday T, Eshtad S, Nik-Zainal S. Mechanisms underlying mutational signatures in human cancers. Nat Rev Genet 2014;15:585-598. https://doi.org/10.1038/nrg3729
  10. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature 2013;500:415-421. https://doi.org/10.1038/nature12477
  11. Pfeifer GP, Denissenko MF, Olivier M, Tretyakova N, Hecht SS, Hainaut P. Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. Oncogene 2002;21:7435-7451. https://doi.org/10.1038/sj.onc.1205803
  12. Pfeifer GP, You YH, Besaratinia A. Mutations induced by ultraviolet light. Mutat Res 2005;571:19-31. https://doi.org/10.1016/j.mrfmmm.2004.06.057
  13. Alexandrov LB, Nik-Zainal S, Wedge DC, Campbell PJ, Stratton MR. Deciphering signatures of mutational processes operative in human cancer. Cell Rep 2013;3:246-259. https://doi.org/10.1016/j.celrep.2012.12.008
  14. Burns MB, Lackey L, Carpenter MA, Rathore A, Land AM, Leonard B, et al. APOBEC3B is an enzymatic source of mutation in breast cancer. Nature 2013;494:366-370. https://doi.org/10.1038/nature11881
  15. Polak P, Kim J, Braunstein LZ, Karlic R, Haradhavala NJ, Tiao G, et al. A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer. Nat Genet 2017;49:1476-1486. https://doi.org/10.1038/ng.3934
  16. Shinbrot E, Henninger EE, Weinhold N, Covington KR, Goksenin AY, Schultz N, et al. Exonuclease mutations in DNA polymerase epsilon reveal replication strand specific mutation patterns and human origins of replication. Genome Res 2014;24:1740-1750. https://doi.org/10.1101/gr.174789.114
  17. Supek F, Lehner B. Clustered mutation signatures reveal that error-prone DNA repair targets mutations to active genes. Cell 2017;170:534-547. https://doi.org/10.1016/j.cell.2017.07.003
  18. Huang KK, Jang KW, Kim S, Kim HS, Kim SM, Kwon HJ, et al. Exome sequencing reveals recurrent REV3L mutations in cisplatin-resistant squamous cell carcinoma of head and neck. Sci Rep 2016;6:19552. https://doi.org/10.1038/srep19552
  19. Taylor AM, Shih J, Ha G, Gao GF, Zhang X, Berger AC, et al. Genomic and functional approaches to understanding cancer aneuploidy. Cancer Cell 2018;33:676-689. https://doi.org/10.1016/j.ccell.2018.03.007
  20. Subramanian A, Kuehn H, Gould J, Tamayo P, Mesirov JP. GSEA-P: a desktop application for Gene Set Enrichment Analysis. Bioinformatics 2007;23:3251-3253. https://doi.org/10.1093/bioinformatics/btm369
  21. Rosenthal R, McGranahan N, Herrero J, Taylor BS, Swanton C. DeconstructSigs: delineating mutational processes in single tumors distinguishes DNA repair deficiencies and patterns of carcinoma evolution. Genome Biol 2016;17:31. https://doi.org/10.1186/s13059-016-0893-4
  22. Knijnenburg TA, Wang L, Zimmermann MT, Chambwe N, Gao GF, Cherniack AD, et al. Genomic and molecular landscape of DNA damage repair deficiency across The Cancer Genome Atlas. Cell Rep 2018;23:239-254. https://doi.org/10.1016/j.celrep.2018.03.076
  23. Marquard AM, Eklund AC, Joshi T, Krzystanek M, Favero F, Wang ZC, et al. Pan-cancer analysis of genomic scar signatures associated with homologous recombination deficiency suggests novel indications for existing cancer drugs. Biomark Res 2015;3:9. https://doi.org/10.1186/s40364-015-0033-4
  24. Bhandari V, Hoey C, Liu LY, Lalonde E, Ray J, Livingstone J, et al. Molecular landmarks of tumor hypoxia across cancer types. Nat Genet 2019;51:308-318. https://doi.org/10.1038/s41588-018-0318-2
  25. Tamayo P, Scanfeld D, Ebert BL, Gillette MA, Roberts CW, Mesirov JP. Metagene projection for cross-platform, cross-species characterization of global transcriptional states. Proc Natl Acad Sci U S A 2007;104:5959-5964. https://doi.org/10.1073/pnas.0701068104
  26. Kim K, Jeon S, Kim TM, Jung CK. Immune gene signature delineates a subclass of papillary thyroid cancer with unfavorable clinical outcomes. Cancers (Basel) 2018;10:494. https://doi.org/10.3390/cancers10120494
  27. Rhee JK, Jung YC, Kim KR, Yoo J, Kim J, Lee YJ, et al. Impact of tumor purity on immune gene expression and clustering analyses across multiple cancer types. Cancer Immunol Res 2018;6:87-97. https://doi.org/10.1158/2326-6066.CIR-17-0201
  28. Davoli T, Uno H, Wooten EC, Elledge SJ. Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy. Science 2017;355:e. aaf8399. https://doi.org/10.1126/science.aaf8399
  29. Herman JG, Umar A, Polyak K, Graff JR, Ahuja N, Issa JP, et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci U S A 1998;95:6870-6875. https://doi.org/10.1073/pnas.95.12.6870
  30. Roberts SA, Lawrence MS, Klimczak LJ, Grimm SA, Fargo D, Stojanov P, et al. An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers. Nat Genet 2013;45:970-976. https://doi.org/10.1038/ng.2702
  31. Buccitelli C, Salgueiro L, Rowald K, Sotillo R, Mardin BR, Korbel JO. Pan-cancer analysis distinguishes transcriptional changes of aneuploidy from proliferation. Genome Res 2017;27:501-511. https://doi.org/10.1101/gr.212225.116
  32. Nowarski R, Kotler M. APOBEC3 cytidine deaminases in double-strand DNA break repair and cancer promotion. Cancer Res 2013;73:3494-3498. https://doi.org/10.1158/0008-5472.CAN-13-0728
  33. Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med 2017;377:2500-2501. https://doi.org/10.1056/NEJMc1713444
  34. 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 2019;14:e0221235. https://doi.org/10.1371/journal.pone.0221235
  35. Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, et al. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 1996;379:88-91. https://doi.org/10.1038/379088a0
  36. Bindra RS, Schaffer PJ, Meng A, Woo J, Maseide K, Roth ME, et al. Down-regulation of Rad51 and decreased homologous recombination in hypoxic cancer cells. Mol Cell Biol 2004;24:8504-8518. https://doi.org/10.1128/MCB.24.19.8504-8518.2004
  37. Mihaylova VT, Bindra RS, Yuan J, Campisi D, Narayanan L, Jensen R, et al. Decreased expression of the DNA mismatch repair gene Mlh1 under hypoxic stress in mammalian cells. Mol Cell Biol 2003;23:3265-3273. https://doi.org/10.1128/MCB.23.9.3265-3273.2003