Mutational processes of distinct POLE exonuclease domain mutants drive an enrichment of a specific TP53 mutation in colorectal cancer

English version

Autoři: Hu Fang ^aff001; Jayne A. Barbour ^aff001; Rebecca C. Poulos ^aff003; Riku Katainen ^aff004; Lauri A. Aaltonen ^aff004; Jason W. H. Wong ^aff001
Působiště autorů: School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region ^aff001; Prince of Wales Clinical School, UNSW Medicine, UNSW Sydney, New South Wales, Australia ^aff002; Children’s Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, New South Wales, Australia ^aff003; Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland ^aff004; Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland ^aff005
Vyšlo v časopise: Mutational processes of distinct POLE exonuclease domain mutants drive an enrichment of a specific TP53 mutation in colorectal cancer. PLoS Genet 16(2): e32767. doi:10.1371/journal.pgen.1008572
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008572

Souhrn

Cancer genomes with mutations in the exonuclease domain of Polymerase Epsilon (POLE) present with an extraordinarily high somatic mutation burden. In vitro studies have shown that distinct POLE mutants exhibit different polymerase activity. Yet, genome-wide mutation patterns and driver mutation formation arising from different POLE mutants remains unclear. Here, we curated somatic mutation calls from 7,345 colorectal cancer samples from published studies and publicly available databases. These include 44 POLE mutant samples including 9 with whole genome sequencing data available. The POLE mutant samples were categorized based on the specific POLE mutation present. Mutation spectrum, associations of somatic mutations with epigenomics features and co-occurrence with specific driver mutations were examined across different POLE mutants. We found that different POLE mutants exhibit distinct mutation spectrum with significantly higher relative frequency of C>T mutations in POLE V411L mutants. Our analysis showed that this increase frequency in C>T mutations is not dependent on DNA methylation and not associated with other genomic features and is thus specifically due to DNA sequence context alone. Notably, we found strong association of the TP53 R213* mutation specifically with POLE P286R mutants. This truncation mutation occurs within the TT[C>T]GA context. For C>T mutations, this sequence context is significantly more likely to be mutated in POLE P286R mutants compared with other POLE exonuclease domain mutants. This study refines our understanding of DNA polymerase fidelity and underscores genome-wide mutation spectrum and specific cancer driver mutation formation observed in POLE mutant cancers.

Klíčová slova:

Cancer genomics – Colorectal cancer – DNA methylation – Methylation – Mutation – Nonsense mutation – Somatic mutation – Substitution mutation

Zdroje

1. Jansen A.M., van Wezel T., van den Akker B.E., Ventayol Garcia M., Ruano D., Tops C.M., Wagner A., Letteboer T.G., Gomez-Garcia E.B., Devilee P. et al. (2016) Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers. Eur J Hum Genet, 24, 1089–1092. doi: 10.1038/ejhg.2015.252 26648449

2. Campbell B.B., Light N., Fabrizio D., Zatzman M., Fuligni F., de Borja R., Davidson S., Edwards M., Elvin J.A., Hodel K.P. et al. (2017) Comprehensive Analysis of Hypermutation in Human Cancer. Cell, 171, 1042–1056 e1010. doi: 10.1016/j.cell.2017.09.048 29056344

3. Cancer Genome Atlas N. (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature, 487, 330–337. doi: 10.1038/nature11252 22810696

4. Cancer Genome Atlas Research, N., Kandoth C., Schultz N., Cherniack A.D., Akbani R., Liu Y., Shen H., Robertson A.G., Pashtan I., Shen R. et al. (2013) Integrated genomic characterization of endometrial carcinoma. Nature, 497, 67–73. doi: 10.1038/nature12113 23636398

5. Alexandrov L.B., Nik-Zainal S., Wedge D.C., Aparicio S.A., Behjati S., Biankin A.V., Bignell G.R., Bolli N., Borg A., Borresen-Dale A.L. et al. (2013) Signatures of mutational processes in human cancer. Nature, 500, 415–421. doi: 10.1038/nature12477 23945592

6. Church D.N., Briggs S.E., Palles C., Domingo E., Kearsey S.J., Grimes J.M., Gorman M., Martin L., Howarth K.M., Hodgson S.V. et al. (2013) DNA polymerase epsilon and delta exonuclease domain mutations in endometrial cancer. Hum Mol Genet, 22, 2820–2828. doi: 10.1093/hmg/ddt131 23528559

7. Xing X.X., Kane D.P., Bulock C.R., Moore E.A., Sharma S., Chabes A. and Shcherbakova P.V. (2019) A recurrent cancer-associated substitution in DNA polymerase epsilon produces a hyperactive enzyme. Nat Commun, 10.

8. Parkash V., Kulkarni Y., ter Beek J., Shcherbakova P.V., Kamerlin S.C.L. and Johansson E. (2019) Structural consequence of the most frequently recurring cancer-associated substitution in DNA polymerase epsilon. Nat Commun, 10.

9. Briggs S. and Tomlinson I. (2013) Germline and somatic polymerase epsilon and delta mutations define a new class of hypermutated colorectal and endometrial cancers. J Pathol, 230, 148–153. doi: 10.1002/path.4185 23447401

10. Haradhvala N.J., Kim J., Maruvka Y.E., Polak P., Rosebrock D., Livitz D., Hess J.M., Leshchiner I., Kamburov A., Mouw K.W. et al. (2018) Distinct mutational signatures characterize concurrent loss of polymerase proofreading and mismatch repair. Nat Commun, 9, 1746. doi: 10.1038/s41467-018-04002-4 29717118

11. Shinbrot E., Henninger E.E., Weinhold N., Covington K.R., Goksenin A.Y., Schultz N., Chao H., Doddapaneni H., Muzny D.M., Gibbs R.A. et al. (2014) Exonuclease mutations in DNA polymerase epsilon reveal replication strand specific mutation patterns and human origins of replication. Genome Res, 24, 1740–1750. doi: 10.1101/gr.174789.114 25228659

12. Gonzalez-Perez A., Sabarinathan R. and Lopez-Bigas N. (2019) Local Determinants of the Mutational Landscape of the Human Genome. Cell, 177, 101–114. doi: 10.1016/j.cell.2019.02.051 30901533

13. Walsh C.P. and Xu G.L. (2006) Cytosine methylation and DNA repair. Curr Top Microbiol Immunol, 301, 283–315. doi: 10.1007/3-540-31390-7_11 16570853

14. Koren A., Polak P., Nemesh J., Michaelson J.J., Sebat J., Sunyaev S.R. and McCarroll S.A. (2012) Differential relationship of DNA replication timing to different forms of human mutation and variation. Am J Hum Genet, 91, 1033–1040. doi: 10.1016/j.ajhg.2012.10.018 23176822

15. Schuster-Böckler B. and Lehner B.J.n. (2012) Chromatin organization is a major influence on regional mutation rates in human cancer cells. 488, 504. doi: 10.1038/nature11273 22820252

16. Hodgkinson A. and Eyre-Walker A. (2011) Variation in the mutation rate across mammalian genomes. Nat Rev Genet, 12, 756–766. doi: 10.1038/nrg3098 21969038

17. Pich O., Muinos F., Sabarinathan R., Reyes-Salazar I., Gonzalez-Perez A. and Lopez-Bigas N. (2018) Somatic and Germline Mutation Periodicity Follow the Orientation of the DNA Minor Groove around Nucleosomes. Cell, 175, 1074–1087 e1018. doi: 10.1016/j.cell.2018.10.004 30388444

18. Poulos R.C., Thoms J.A., Guan Y.F., Unnikrishnan A., Pimanda J.E. and Wong J.W.J.C.r. (2016) Functional mutations form at CTCF-cohesin binding sites in melanoma due to uneven nucleotide excision repair across the motif. 17, 2865–2872. doi: 10.1016/j.celrep.2016.11.055 27974201

19. Frigola J., Sabarinathan R., Mularoni L., Muinos F., Gonzalez-Perez A. and Lopez-Bigas N. (2017) Reduced mutation rate in exons due to differential mismatch repair. Nat Genet, 49, 1684–+. doi: 10.1038/ng.3991 29106418

20. Poulos R.C., Olivier J. and Wong J.W.H. (2017) The interaction between cytosine methylation and processes of DNA replication and repair shape the mutational landscape of cancer genomes. Nucleic Acids Res, 45, 7786–7795. doi: 10.1093/nar/gkx463 28531315

21. Tomkova M., McClellan M., Kriaucionis S. and Schuster-Bockler B. (2018) DNA Replication and associated repair pathways are involved in the mutagenesis of methylated cytosine. DNA Repair (Amst), 62, 1–7.

22. Tomkova M. and Schuster-Bockler B. (2018) DNA Modifications: Naturally More Error Prone? Trends Genet, 34, 627–638. doi: 10.1016/j.tig.2018.04.005 29853204

23. Kaiser V.B., Taylor M.S. and Semple C.A. (2016) Mutational biases drive elevated rates of substitution at regulatory sites across cancer types. PLoS genetics, 12, e1006207%@ 1001553–1007404. doi: 10.1371/journal.pgen.1006207 27490693

24. Katainen R., Dave K., Pitkanen E., Palin K., Kivioja T., Valimaki N., Gylfe A.E., Ristolainen H., Hanninen U.A., Cajuso T. et al. (2015) CTCF/cohesin-binding sites are frequently mutated in cancer. Nat Genet, 47, 818–+. doi: 10.1038/ng.3335 26053496

25. Perera D., Poulos R.C., Shah A., Beck D., Pimanda J.E. and Wong J.W. (2016) Differential DNA repair underlies mutation hotspots at active promoters in cancer genomes. Nature, 532, 259–263. doi: 10.1038/nature17437 27075100

26. Sabarinathan R., Mularoni L., Deu-Pons J., Gonzalez-Perez A. and Lopez-Bigas N. (2016) Nucleotide excision repair is impaired by binding of transcription factors to DNA. Nature, 532, 264%@ 1476–4687. doi: 10.1038/nature17661 27075101

27. Haradhvala N.J., Polak P., Stojanov P., Covington K.R., Shinbrot E., Hess J.M., Rheinbay E., Kim J., Maruvka Y.E., Braunstein L.Z. et al. (2016) Mutational Strand Asymmetries in Cancer Genomes Reveal Mechanisms of DNA Damage and Repair. Cell, 164, 538–549. doi: 10.1016/j.cell.2015.12.050 26806129

28. Supek F. and Lehner B. (2015) Differential DNA mismatch repair underlies mutation rate variation across the human genome. Nature, 521, 81–U173. doi: 10.1038/nature14173 25707793

29. Tomkova M., Tomek J., Kriaucionis S. and Schuster-Bockler B. (2018) Mutational signature distribution varies with DNA replication timing and strand asymmetry. Genome Biol, 19.

30. Brown A.J., Mao P., Smerdon M.J., Wyrick J.J. and Roberts S.A. (2018) Nucleosome positions establish an extended mutation signature in melanoma. Plos Genetics, 14.

31. Sassa A., Kanemaru Y., Kamoshita N., Honma M. and Yasui M. (2016) Mutagenic consequences of cytosine alterations site-specifically embedded in the human genome. Genes Environ, 38.

32. Sparks J.L., Chistol G., Gao A.O., Räschle M., Larsen N.B., Mann M., Duxin J.P. and Walter J.C. (2019) The CMG helicase bypasses DNA-protein cross-links to facilitate their repair. Cell, 176, 167–181. e121%@ 0092–8674. doi: 10.1016/j.cell.2018.10.053 30595447

33. Alexandrov L.B., Nik-Zainal S., Wedge D.C., Campbell P.J. and Stratton M.R. (2013) Deciphering Signatures of Mutational Processes Operative in Human Cancer. Cell Reports, 3, 246–259. doi: 10.1016/j.celrep.2012.12.008 23318258

34. Poulos R.C., Wong Y.T., Ryan R., Pang H. and Wong J.W.H. (2018) Analysis of 7,815 cancer exomes reveals associations between mutational processes and somatic driver mutations. Plos Genetics, 14.

35. Temko D., Tomlinson I.P.M., Severini S., Schuster-Bockler B. and Graham T.A. (2018) The effects of mutational processes and selection on driver mutations across cancer types. Nat Commun, 9.

36. Lee M., Wang X., Zhang S., Zhang Z. and Lee E. (2017) Regulation and modulation of human DNA polymerase δ activity and function. Genes, 8, 190.

37. Palles C., Cazier J.B., Howarth K.M., Domingo E., Jones A.M., Broderick P., Kemp Z., Spain S.L., Almeida E.G., Salguero I. et al. (2013) Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet, 45, 136–144. doi: 10.1038/ng.2503 23263490

38. Wilks C., Cline M.S., Weiler E., Diehkans M., Craft B., Martin C., Murphy D., Pierce H., Black J., Nelson D. et al. (2014) The Cancer Genomics Hub (CGHub): overcoming cancer through the power of torrential data. Database-Oxford.

39. Giannakis M., Mu X.J., Shukla S.A., Qian Z.R., Cohen O., Nishihara R., Bahl S., Cao Y., Amin-Mansour A., Yamauchi M. et al. (2016) Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma. Cell Reports, 15, 857–865. doi: 10.1016/j.celrep.2016.03.075 27149842

40. Seshagiri S., Stawiski E.W., Durinck S., Modrusan Z., Storm E.E., Conboy C.B., Chaudhuri S., Guan Y.H., Janakiraman V., Jaiswal B.S. et al. (2012) Recurrent R-spondin fusions in colon cancer. Nature, 488, 660–+. doi: 10.1038/nature11282 22895193

41. Yaeger R., Chatila W.K., Lipsyc M.D., Hechtman J.F., Cercek A., Sanchez-Vega F., Jayakumaran G., Middha S., Zehir A., Donoghue M.T.A. et al. (2018) Clinical Sequencing Defines the Genomic Landscape of Metastatic Colorectal Cancer. Cancer Cell, 33, 125–+. doi: 10.1016/j.ccell.2017.12.004 29316426

42. Cerami E., Gao J.J., Dogrusoz U., Gross B.E., Sumer S.O., Aksoy B.A., Jacobsen A., Byrne C.J., Heuer M.L., Larsson E. et al. (2012) The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data. Cancer Discov, 2, 401–404. doi: 10.1158/2159-8290.CD-12-0095 22588877

43. Kundaje A., Meuleman W., Ernst J., Bilenky M., Yen A., Heravi-Moussavi A., Kheradpour P., Zhang Z., Wang J., Ziller M.J. et al. (2015) Integrative analysis of 111 reference human epigenomes. Nature, 518, 317–330. doi: 10.1038/nature14248 25693563

44. Gaffney D.J., McVicker G., Pai A.A., Fondufe-Mittendorf Y.N., Lewellen N., Michelini K., Widom J., Gilad Y. and Pritchard J.K. (2012) Controls of Nucleosome Positioning in the Human Genome. Plos Genetics, 8.

45. Cui F. and Zhurkin V.B. (2010) Structure-based Analysis of DNA Sequence Patterns Guiding Nucleosome Positioning in vitro. J Biomol Struct Dyn, 27, 821–841. doi: 10.1080/073911010010524947 20232936

46. Sloan C.A., Chan E.T., Davidson J.M., Malladi V.S., Strattan J.S., Hitz B.C., Gabdank I., Narayanan A.K., Ho M., Lee B.T. et al. (2016) ENCODE data at the ENCODE portal. Nucleic Acids Research, 44, D726–D732. doi: 10.1093/nar/gkv1160 26527727

Článek PRH1 mediates ARF7-LBD dependent auxin signaling to regulate lateral root development in Arabidopsis thaliana

Článek Evolutionary dynamics of microRNA target sites across vertebrate evolution

Článek Aberrant cell segregation in the craniofacial primordium and the emergence of facial dysmorphology in craniofrontonasal syndrome

Článek Dramatically diverse Schizosaccharomyces pombe wtf meiotic drivers all display high gamete-killing efficiency

Článek Identification of a novel base J binding protein complex involved in RNA polymerase II transcription termination in trypanosomes

Článek Magnetic genes: Studying the genetics of biomineralization in magnetotactic bacteria

Článek Tensor decomposition of stimulated monocyte and macrophage gene expression profiles identifies neurodegenerative disease-specific trans-eQTLs

Článek The persimmon genome reveals clues to the evolution of a lineage-specific sex determination system in plants

Článek A molecular barcode to inform the geographical origin and transmission dynamics of Plasmodium vivax malaria

Článek Identifying neural substrates of competitive interactions and sequence transitions during mechanosensory responses in Drosophila

Článek NCBP2 modulates neurodevelopmental defects of the 3q29 deletion in Drosophila and Xenopus laevis models

Článek Parallel and nonparallel genomic responses contribute to herbicide resistance in Ipomoea purpurea, a common agricultural weed