Pan-cancer analysis of somatic mutations and epigenetic alterations in insulated neighbourhood boundaries
Autoři:
Pietro Pinoli aff001; Eirini Stamoulakatou aff001; An-Phi Nguyen aff002; María Rodríguez Martínez aff002; Stefano Ceri aff001
Působiště autorů:
DEIB, Politecnico di Milano, Milano, Italy
aff001; IBM Research Zürich, Rüschlikon, Switzerland
aff002
Vyšlo v časopise:
PLoS ONE 15(1)
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pone.0227180
Souhrn
Recent evidence shows that the disruption of constitutive insulated neighbourhoods might lead to oncogene dysregulation. We present here a systematic pan-cancer characterisation of the associations between constitutive boundaries and genome alterations in cancer. Specifically, we investigate the enrichment of somatic mutation, abnormal methylation, and copy number alteration events in the proximity of CTCF bindings overlapping with topological boundaries (junctions) in 26 cancer types. Focusing on CTCF motifs that are both in-boundary (overlapping with junctions) and active (overlapping with peaks of CTCF expression), we find a significant enrichment of somatic mutations in several cancer types. Furthermore, mutated junctions are significantly conserved across cancer types, and we also observe a positive selection of transversions rather than transitions in many cancer types. We also analyzed the mutational signature found on the different classes of CTCF motifs, finding some signatures (such as SBS26) to have a higher weight within in-boundary than off-bounday motifs. Regarding methylation, we find a significant number of over-methylated active in-boundary CTCF motifs in several cancer types; similarly to somatic-mutated junctions, they also have a significant conservation across cancer types. Finally, in several cancer types we observe that copy number alterations tend to overlap with active junctions more often than in matched normal samples. While several articles have recently reported a mutational enrichment at CTCF binding sites for specific cancer types, our analysis is pan-cancer and investigates abnormal methylation and copy number alterations in addition to somatic mutations. Our method is fully replicable and suggests several follow-up tumour-specific analyses.
Klíčová slova:
Adenocarcinomas – Breast cancer – Cancer genomics – DNA methylation – Methylation – Point mutation – Somatic mutation – Substitution mutation
Zdroje
1. Bickmore WA, van Steensel B. Genome Architecture: Domain Organization of Interphase Chromosomes. Cell. 2013;152(6):1270–1284. https://doi.org/10.1016/j.cell.2013.02.001 23498936
2. Dixon JR, Selvaraj S, Yue F, Kim A, Li Y, Shen Y, et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature. 2012;485:376 EP –. doi: 10.1038/nature11082 22495300
3. Lieberman-Aiden E, van Berkum NL, Williams L, Imakaev M, Ragoczy T, Telling A, et al. Comprehensive mapping of long range interactions reveals folding principles of the human genome. Science. 2009;326(5950):289–293. doi: 10.1126/science.1181369 19815776
4. Baniahmad A, Steiner C, Köhne AC, Renkawitz R. Modular structure of a chicken lysozyme silencer: involvement of an unusual thyroid hormone receptor binding site. Cell. 1990;61(3):505–514. doi: 10.1016/0092-8674(90)90532-j 2159385
5. Filippova GN, Thienes CP, Penn BH, Cho DH, Hu YJ, Moore JM, et al. CTCF -binding sites flank CTG/CAG repeats and form a methylation-sensitive insulator at the DM1 locus. Nature Genetics. 2001;28(4):335–343. doi: 10.1038/ng570 11479593
6. Bell AC, Felsenfeld G. Methylation of a CTCF -dependent boundary controls imprinted expression of the Igf2 gene. Nature. 2000;405(6785):482–485. doi: 10.1038/35013100 10839546
7. Hark AT, Schoenherr CJ, Katz DJ, Ingram RS, Levorse JM, Tilghman SM. CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus. Nature. 2000;405(6785):486–489. doi: 10.1038/35013106 10839547
8. Yusufzai TM, Tagami H, Nakatani Y, Felsenfeld G. CTCF tethers an insulator to subnuclear sites, suggesting shared insulator mechanisms across species. Molecular Cell. 2004;13(2):291–298. doi: 10.1016/s1097-2765(04)00029-2 14759373
9. Hou C, Zhao H, Tanimoto K, Dean A. CTCF -dependent enhancer-blocking by alternative chromatin loop formation. Proceedings of the National Academy of Sciences. 2008;105(51):20398–20403. doi: 10.1073/pnas.0808506106
10. Phillips-Cremins JE, Sauria MEG, Sanyal A, Gerasimova TI, Lajoie BR, Bell JSK, et al. Architectural Protein Subclasses Shape 3D Organization of Genomes during Lineage Commitment. Cell. 2013;153(6):1281–1295. doi: 10.1016/j.cell.2013.04.053 23706625
11. Rao SSP, Huntley MH, Durand NC, Stamenova EK, Bochkov ID, Robinson JT, et al. A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping. Cell. 2014;159(7):1665–1680. https://doi.org/10.1016/j.cell.2014.11.021 25497547
12. Dowen JM, Fan ZP, Hnisz D, Ren G, Abraham BJ, Zhang LN, et al. Control of Cell Identity Genes Occurs in Insulated Neighborhoods in Mammalian Chromosomes. Cell. 2014;159(2):374–387. doi: 10.1016/j.cell.2014.09.030 25303531
13. Ji X, Dadon DB, Powell BE, Fan ZP, Borges-Rivera D, Shachar S, et al. 3D Chromosome Regulatory Landscape of Human Pluripotent Cells. Cell Stem Cell. 2016;18(2):262–275. doi: 10.1016/j.stem.2015.11.007 26686465
14. Dixon JR, Gorkin DU, Ren B. Chromatin Domains: The Unit of Chromosome Organization. Molecular Cell. 2016;62(5):668–680. https://doi.org/10.1016/j.molcel.2016.05.018 27259200
15. Jose CC, Xu B, Jagannathan L, Trac C, Mallela RK, Hattori T, et al. Epigenetic dysregulation by nickel through repressive chromatin domain disruption. Proceedings of the National Academy of Sciences of the United States of America. 2014;111(40):14631–14636. doi: 10.1073/pnas.1406923111 25246589
16. Filippova GN, Qi CF, Ulmer JE, Moore JM, Ward MD, Hu YJ, et al. Tumor-associated Zinc Finger Mutations in the CTCF Transcription Factor Selectively Alter Its DNA-binding Specificity. Cancer Research. 2002;62(1):48–52. 11782357
17. Prawitt D, Enklaar T, Gärtner-Rupprecht B, Spangenberg C, Oswald M, Lausch E, et al. Microdeletion of target sites for insulator protein CTCF in a chromosome 11p15 imprinting center in Beckwith—Wiedemann syndrome and Wilms’ tumor. Proceedings of the National Academy of Sciences. 2005;102(11):4085–4090. doi: 10.1073/pnas.0500037102
18. Katainen R, Dave K, Pitkänen E, Palin K, Kivioja T, Välimäki N, et al. CTCF /cohesin-binding sites are frequently mutated in cancer. Nature Genetics. 2015;47:818. doi: 10.1038/ng.3335 26053496
19. Gregor A, Oti M, Kouwenhoven EN, Hoyer J, Sticht H, Ekici AB, et al. De Novo Mutations in the Genome Organizer CTCF Cause Intellectual Disability. The American Journal of Human Genetics. 2013;93(1):124–131. doi: 10.1016/j.ajhg.2013.05.007 23746550
20. Bastaki F, Nair P, Mohamed M, Malik EM, Helmi M, Al-Ali MT, et al. Identification of a novel CTCF mutation responsible for syndromic intellectual disability—a case report. BMC Medical Genetics. 2017;18(1):68. doi: 10.1186/s12881-017-0429-0 28619046
21. Herold M, Bartkuhn M, Renkawitz R. CTCF: insights into insulator function during development. Development. 2012;139(6):1045–1057. doi: 10.1242/dev.065268 22354838
22. Flavahan WA, Drier Y, Liau BB, Gillespie SM, Venteicher AS, Stemmer-Rachamimov AO, et al. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature. 2015;529:110 EP –. doi: 10.1038/nature16490 26700815
23. Hnisz D, Weintraub AS, Day DS, Valton AL, Bak RO, Li CH, et al. Activation of proto-oncogenes by disruption of chromosome neighborhoods. Science. 2016;351(6280):1454–1458. doi: 10.1126/science.aad9024 26940867
24. Gröschel S, Sanders MA, Hoogenboezem R, de Wit E, Bouwman BAM, Erpelinck C, et al. A Single Oncogenic Enhancer Rearrangement Causes Concomitant EVI1 and GATA2 Deregulation in Leukemia. Cell. 2014;157(2):369–381. doi: 10.1016/j.cell.2014.02.019 24703711
25. Northcott PA, Lee C, Zichner T, Stütz AM, Erkek S, Kawauchi D, et al. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature. 2014;511:428. doi: 10.1038/nature13379 25043047
26. Walker BA, Wardell CP, Brioli A, Boyle E, Kaiser MF, Begum DB, et al. Translocations at 8q24 juxtapose MYC with genes that harbor superenhancers resulting in overexpression and poor prognosis in myeloma patients. Blood Cancer Journal. 2014;4:e191. doi: 10.1038/bcj.2014.13 24632883
27. Taberlay PC, Achinger-Kawecka J, Lun ATL, Buske FA, Sabir K, Gould CM, et al. Three-dimensional disorganization of the cancer genome occurs coincident with long-range genetic and epigenetic alterations. Genome Research. 2016;26(6):719–731. doi: 10.1101/gr.201517.115 27053337
28. Poulos RC, Thoms JA, Guan YF, Unnikrishnan A, Pimanda JE, Wong JW. Functional mutations form at CTCF-cohesin binding sites in melanoma due to uneven nucleotide excision repair across the motif. Cell reports. 2016;17(11):2865–2872. doi: 10.1016/j.celrep.2016.11.055 27974201
29. Sabarinathan R, Mularoni L, Deu-Pons J, Gonzalez-Perez A, Lopez-Bigas N. Nucleotide excision repair is impaired by binding of transcription factors to DNA. Nature. 2016;532(7598):264. doi: 10.1038/nature17661 27075101
30. Guo YA, Chang MM, Huang W, Ooi WF, Xing M, Tan P, et al. Mutation hotspots at CTCF binding sites coupled to chromosomal instability in gastrointestinal cancers. Nature communications. 2018;9(1):1520. doi: 10.1038/s41467-018-03828-2 29670109
31. Liu EM, Martinez-Fundichely A, Diaz BJ, Aronson B, Cuykendall T, MacKay M, et al. Identification of Cancer Drivers at CTCF Insulators in 1,962 Whole Genomes. Cell systems. 2019;8(5):446–455. doi: 10.1016/j.cels.2019.04.001 31078526
32. Gonzalez-Perez A, Sabarinathan R, Lopez-Bigas N. Local Determinants of the Mutational Landscape of the Human Genome. Cell. 2019;177(1):101–114. doi: 10.1016/j.cell.2019.02.051 30901533
33. ICGC: International Cancer Genome Consortium homepage;. https://dcc.icgc.org/.
34. TCGA: The Cancer Genome Atlas homepage;. https://portal.gdc.cancer.gov/.
35. ENCODE: Encyclopedia of DNA Elements homepage;. https://www.encodeproject.org/.
36. Masseroli M, Pinoli P, Venco F, Kaitoua A, Jalili V, Palluzzi F, et al. GenoMetric Query Language: a novel approach to large-scale genomic data management. Bioinformatics. 2015;31(12):1881–1888. doi: 10.1093/bioinformatics/btv048 25649616
37. Tang Z, Luo OJ, Li X, Zheng M, Zhu JJ, Szalaj P, et al. CTCF -Mediated Human 3D Genome Architecture Reveals Chromatin Topology for Transcription. Cell. 2015;163(7):1611–1627. doi: 10.1016/j.cell.2015.11.024 26686651
38. Pagès H, Aboyoun P, Gentleman R, DebRoy S. Biostrings: Efficient manipulation of biological strings; 2017.
39. Sandelin A, Alkema W, Engström P, Wasserman WW, Lenhard B. JASPAR: an open-access database for eukaryotic transcription factor binding profiles. Nucleic acids research. 2004;32(suppl_1):D91–D94. doi: 10.1093/nar/gkh012 14681366
40. Perera D, Poulos RC, Shah A, Beck D, Pimanda JE, Wong JWH. Differential DNA repair underlies mutation hotspots at active promoters in cancer genomes. Nature. 2016;532:259 EP –. doi: 10.1038/nature17437 27075100
41. Guo C, McDowell IC, Nodzenski M, Scholtens DM, S AA, Lowe WL, et al. Transversions have larger regulatory effects than transitions. BMC Genomics. 2017;18:394:1–9. doi: 10.1186/s12864-017-3785-4
42. Alexandrov LB, Stratton MR. Mutational signatures: the patterns of somatic mutations hidden in cancer genomes. Current Opinion in Genetics & Development. 2014;24:52–60. https://doi.org/10.1016/j.gde.2013.11.014.
43. Alexandrov LB, Kim J, et al. The Repertoire of Mutational Signatures in Human Cancer. BMC Bioinformatics. 2019;4:20:152.
44. Krüger S, Piro RM decompTumor2Sig: identification of mutational signatures active in individual tumors. bioRxiv. 2018.
45. Stadler MB, Murr R, Burger L, Ivanek R, Lienert F, Schöler A, et al. DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature. 2011;480:490. doi: 10.1038/nature10716 22170606
46. Wang H, Maurano MT, Qu H, Varley KE, Gertz J, Pauli F, et al. Widespread plasticity in CTCF occupancy linked to DNA methylation. Genome Research. 2012;22(9):1680–1688. doi: 10.1101/gr.136101.111 22955980
47. Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, et al. The landscape of somatic copy-number alteration across human cancers. Nature. 2010;463(7283):899–905. doi: 10.1038/nature08822 20164920
48. Weischenfeldt J, Dubash T, Drainas AP, Mardin BR, Chen Y, Stütz AM, et al. Pan-cancer analysis of somatic copy number alterations implicates IRS4 and IGF2 in enhancer hijacking. Nat Genet. 2017;49(1):65–74. doi: 10.1038/ng.3722 27869826
49. Laddha Saurabh V., Ganesan Shridar, Chan Chang S., and White Eileen. Mutational landscape of the essential autophagy gene becn1 in human cancers. Molecular cancer research: MCR, 12(4):485–490, Apr 2014. doi: 10.1158/1541-7786.MCR-13-0614 24478461
50. Graham NA, Minasyan A, Lomova A, Cass A, Balanis NG, Friedman M, et al. Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures. Molecular Systems Biology. 2017;13(2). doi: 10.15252/msb.20167159 28202506
51. Corces MR, Corces VG. The three-dimensional cancer genome. Current Opinion in Genetics & Development. 2016;36:1–7. https://doi.org/10.1016/j.gde.2016.01.002.
52. Valton AL, Dekker J. TAD disruption as oncogenic driver. Current Opinion in Genetics & Development. 2016;36:34–40. https://doi.org/10.1016/j.gde.2016.03.008.
53. Krijger PHL, de Laat W. Regulation of disease-associated gene expression in the 3D genome. Nature Reviews Molecular Cell Biology. 2016;17:771 EP –. doi: 10.1038/nrm.2016.138 27826147
54. Kaiser VB, Semple CA. When TADs go bad: chromatin structure and nuclear organisation in human disease. F1000Res. 2017; 6:F1000 Faculty Rev–314.
55. Song SH, Kim TY. CTCF, Cohesin, and Chromatin in Human Cancer. Genomics Inform. 2017;15(4):114–122. doi: 10.5808/GI.2017.15.4.114 29307136
56. Zack TI, Schumacher SE, Carter SL, Cherniack AD, Saksena G, Tabak B, et al. Pan-cancer patterns of somatic copy number alteration. Nature genetics. 2013;45(10):1134. doi: 10.1038/ng.2760 24071852
57. Yang J, Wei X, Tufan T, Kuscu C, Unlu H, Farooq S, et al. Recurrent mutations at estrogen receptor binding sites alter chromatin topology and distal gene expression in breast cancer. Genome biology. 2018;19(1):190. doi: 10.1186/s13059-018-1572-4 30404658
Článek vyšel v časopise
PLOS One
2020 Číslo 1
- S diagnostikou Parkinsonovy nemoci může nově pomoci AI nástroj pro hodnocení mrkacího reflexu
- Proč při poslechu některé muziky prostě musíme tančit?
- Je libo čepici místo mozkového implantátu?
- Chůze do schodů pomáhá prodloužit život a vyhnout se srdečním chorobám
- Pomůže v budoucnu s triáží na pohotovostech umělá inteligence?
Nejčtenější v tomto čísle
- Severity of misophonia symptoms is associated with worse cognitive control when exposed to misophonia trigger sounds
- Chemical analysis of snus products from the United States and northern Europe
- Calcium dobesilate reduces VEGF signaling by interfering with heparan sulfate binding site and protects from vascular complications in diabetic mice
- Effect of Lactobacillus acidophilus D2/CSL (CECT 4529) supplementation in drinking water on chicken crop and caeca microbiome
Zvyšte si kvalifikaci online z pohodlí domova
Všechny kurzy