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Genomic Hallmarks of Genes Involved in Chromosomal Translocations in Hematological Cancer

DOI: 10.1371/journal.pcbi.1002797

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Abstract:

Reciprocal chromosomal translocations (RCTs) leading to the formation of fusion genes are important drivers of hematological cancers. Although the general requirements for breakage and fusion are fairly well understood, quantitative support for a general mechanism of RCT formation is still lacking. The aim of this paper is to analyze available high-throughput datasets with computational and robust statistical methods, in order to identify genomic hallmarks of translocation partner genes (TPGs). Our results show that fusion genes are generally overexpressed due to increased promoter activity of 5′ TPGs and to more stable 3′-UTR regions of 3′ TPGs. Furthermore, expression profiling of 5′ TPGs and of interaction partners of 3′ TPGs indicates that these features can help to explain tissue specificity of hematological translocations. Analysis of protein domains retained in fusion proteins shows that the co-occurrence of specific domain combinations is non-random and that distinct functional classes of fusion proteins tend to be associated with different components of the gene fusion network. This indicates that the configuration of fusion proteins plays an important role in determining which 5′ and 3′ TPGs will combine in specific fusion genes. It is generally accepted that chromosomal proximity in the nucleus can explain the specific pairing of 5′ and 3′ TPGS and the recurrence of hematological translocations. Using recently available data for chromosomal contact probabilities (Hi-C) we show that TPGs are preferentially located in early replicated regions and occupy distinct clusters in the nucleus. However, our data suggest that, in general, nuclear position of TPGs in hematological cancers explains neither TPG pairing nor clinical frequency. Taken together, our results support a model in which genomic features related to regulation of expression and replication timing determine the set of candidate genes more likely to be translocated in hematological tissues, with functional constraints being responsible for specific gene combinations.

 References

[1]  Mitelman F, Johansson B, Mertens F (2007) The impact of translocations and gene fusions on cancer causation. Nature Reviews Cancer 7: 233–245. doi: 10.1038/nrc2091
[2]  Nambiar M, Kari V, Raghavan SC (2008) Chromosomal translocations in cancer. Biochimica et Biophysica Acta 1786: 139–152. doi: 10.1016/j.bbcan.2008.07.005
[3]  Rowley JD (2001) Chromosome translocations: dangerous liaisons revisited. Nature Reviews Cancer 1: 245–250. doi: 10.1038/35106108
[4]  Rabbitts TH (2009) Commonality but diversity in cancer gene fusions. Cell 137: 391–395. doi: 10.1016/j.cell.2009.04.034
[5]  Novo FJ, de Mendíbil IO, Vizmanos JL (2007) TICdb: a collection of gene-mapped translocation breakpoints in cancer. BMC Genomics 8: 33.
[6]  Parada LA, McQueen PG, Misteli T (2004) Tissue-specific spatial organization of genomes. Genome Biology 5: R44. doi: 10.1186/gb-2004-5-7-r44
[7]  Roix JJ, McQueen PG, Munson PJ, Parada LA, Misteli T (2003) Spatial proximity of translocation-prone gene loci in human lymphomas. Nature Genetics 34: 287–291. doi: 10.1038/ng1177
[8]  Lin C, Yang L, Rosenfeld MG (2012) Molecular logic underlying chromosomal translocations, random or non-random? Advances in Cancer Research 113: 241–279. doi: 10.1016/b978-0-12-394280-7.00015-4
[9]  Gostissa M, Alt FW, Chiarle R (2011) Mechanisms that promote and suppress chromosomal translocations in lymphocytes. Annual Review of Immunology 29: 319–350. doi: 10.1146/annurev-immunol-031210-101329
[10]  Mitelman F, Johansson B, Mertens F (2004) Fusion genes and rearranged genes as a linear function of chromosome aberrations in cancer. Nature Genetics 36: 331–334. doi: 10.1038/ng1335
[11]  Forster A, Pannell R, Drynan LF, Codrington R, Daser A, et al. (2005) The invertor knock-in conditional chromosomal translocation mimic. Nature Methods 2: 27–30. doi: 10.1038/nmeth727
[12]  Berezikov E (2011) Evolution of microRNA diversity and regulation in animals. Nature Reviews Genetics 12: 846–860. doi: 10.1038/nrg3079
[13]  Vasilatou D, Papageorgiou S, Pappa V, Papageorgiou E, Dervenoulas J (2010) The role of microRNAs in normal and malignant hematopoiesis. European Journal of Haematology 84: 1–16. doi: 10.1111/j.1600-0609.2009.01348.x
[14]  Ortiz de Mendíbil I, Vizmanos JL, Novo FJ (2009) Signatures of selection in fusion transcripts resulting from chromosomal translocations in human cancer. PLoS ONE 4: e4805. doi: 10.1371/journal.pone.0004805
[15]  Huang DW, Sherman BT, Lempicki RA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nature Protocols 4: 44–57. doi: 10.1038/nprot.2008.211
[16]  Lieberman-Aiden E, van Berkum NL, Williams L, Imakaev M, Ragoczy T, et al. (2009) Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326: 289–293. doi: 10.1126/science.1181369
[17]  Yaffe E, Tanay A (2011) Probabilistic modeling of Hi-C contact maps eliminates systematic biases to characterize global chromosomal architecture. Nature Genetics 43: 1059–1065. doi: 10.1038/ng.947
[18]  Ryba T, Hiratani I, Lu J, Itoh M, Kulik M, et al. (2010) Evolutionarily conserved replication timing profiles predict long-range chromatin interactions and distinguish closely related cell types. Genome Research 20: 761–770. doi: 10.1101/gr.099655.109
[19]  Stamatoyannopoulos JA, Adzhubei I, Thurman RE, Kryukov GV, Mirkin SM, et al. (2009) Human mutation rate associated with DNA replication timing. Nature Genetics 41: 393–395. doi: 10.1038/ng.363
[20]  De S, Michor F (2011) DNA replication timing and long-range DNA interactions predict mutational landscapes of cancer genomes. Nature Biotechnology 29: 1103–1108. doi: 10.1038/nbt.2030
[21]  Rabbitts TH (1994) Chromosomal translocations in human cancer. Nature 372: 143–149. doi: 10.1038/372143a0
[22]  Mayr C, Hemann MT, Bartel DP (2007) Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science 315: 1576–1579. doi: 10.1126/science.1137999
[23]  Gomez-Benito M, Loayza-Puch F, Oude Vrielink J, Odero MD, Agami R (2011) 3′UTR-Mediated Gene Silencing of the Mixed Lineage Leukemia (MLL) Gene. PLoS ONE 6: e25449. doi: 10.1371/journal.pone.0025449
[24]  Ruiz JF, Gómez-González B, Aguilera A (2011) AID induces double-strand breaks at immunoglobulin switch regions and c-MYC causing chromosomal translocations in yeast THO mutants. PLoS Genetics 7: e1002009. doi: 10.1371/journal.pgen.1002009
[25]  Chiarle R, Zhang Y, Frock RL, Lewis SM, Molinie B, et al. (2011) Genome-wide translocation sequencing reveals mechanisms of chromosome breaks and rearrangements in B cells. Cell 147: 107–119. doi: 10.1016/j.cell.2011.07.049
[26]  Klein IA, Resch W, Jankovic M, Oliveira T, Yamane A, et al. (2011) Translocation-capture sequencing reveals the extent and nature of chromosomal rearrangements in B lymphocytes. Cell 147: 95–106. doi: 10.1016/j.cell.2011.07.048
[27]  Nik-Zainal S, Alexandrov LB, Wedge DC, Van Loo P, Greenman CD, et al. (2012) Mutational Processes Molding the Genomes of 21 Breast Cancers. Cell 149: 979–993. doi: 10.1016/j.cell.2012.04.024
[28]  Hastings PJ, Lupski JR, Rosenberg SM, Ira G (2009) Mechanisms of change in gene copy number. Nature Reviews Genetics 10: 551–564. doi: 10.1038/nrg2593
[29]  Lang GI, Murray AW (2011) Mutation rates across budding yeast chromosome VI are correlated with replication timing. Genome Biology and Evolution 3: 799–811. doi: 10.1093/gbe/evr054
[30]  Aran D, Toperoff G, Rosenberg M, Hellman A (2011) Replication timing-related and gene body-specific methylation of active human genes. Human Molecular Genetics 20: 670–680. doi: 10.1093/hmg/ddq513
[31]  Rabbitts TH (1991) Translocations, master genes, and differences between the origins of acute and chronic leukemias. Cell 67: 641–644. doi: 10.1016/0092-8674(91)90057-6
[32]  Hegyi H, Buday L, Tompa P (2009) Intrinsic structural disorder confers cellular viability on oncogenic fusion proteins. PLoS Computational Biology 5: e1000552. doi: 10.1371/journal.pcbi.1000552
[33]  Pawson T, Warner N (2007) Oncogenic re-wiring of cellular signaling pathways. Oncogene 26: 1268–1275. doi: 10.1038/sj.onc.1210255
[34]  Füllgrabe J, Kavanagh E, Joseph B (2011) Histone onco-modifications. Oncogene 30: 3391–3403. doi: 10.1038/onc.2011.121
[35]  Slany RK (2005) When epigenetics kills: MLL fusion proteins in leukemia. Hematological Oncology 23: 1–9. doi: 10.1002/hon.739
[36]  Tenney K, Shilatifard A (2005) A COMPASS in the voyage of defining the role of trithorax/MLL-containing complexes: linking leukemogensis to covalent modifications of chromatin. Journal of Cellular Biochemistry 95: 429–436. doi: 10.1002/jcb.20421
[37]  Dostie J, Bickmore WA (2012) Chromosome organization in the nucleus - charting new territory across the Hi-Cs. Current Opinion in Genetics & Development 22: 125–131. doi: 10.1016/j.gde.2011.12.006
[38]  Kalhor R, Tjong H, Jayathilaka N, Alber F, Chen L (2012) Genome architectures revealed by tethered chromosome conformation capture and population-based modeling. Nature Biotechnology 30: 90–98. doi: 10.1038/nbt.2057
[39]  Ryba T, Hiratani I, Sasaki T, Battaglia D, Kulik M, et al. (2011) Replication timing: a fingerprint for cell identity and pluripotency. PLoS Computational Biology 7: e1002225. doi: 10.1371/journal.pcbi.1002225
[40]  Gilbert DM, Takebayashi S-I, Ryba T, Lu J, Pope BD, et al. (2010) Space and time in the nucleus: developmental control of replication timing and chromosome architecture. Cold Spring Harbor Symposia on Quantitative Biology 75: 143–153. doi: 10.1101/sqb.2010.75.011
[41]  de Laat W, Grosveld F (2003) Spatial organization of gene expression: the active chromatin hub. Chromosome Research 11: 447–459. doi: 10.1023/a:1024922626726
[42]  Cremer T, Cremer M (2010) Chromosome territories. Cold Spring Harbor perspectives in biology 2: a003889. doi: 10.1101/cshperspect.a003889
[43]  Kress C, Ballester M, Devinoy E, Rijnkels M (2010) Epigenetic modifications in 3D: nuclear organization of the differentiating mammary epithelial cell. Journal of Mammary Gland Biology and Neoplasia 15: 73–83. doi: 10.1007/s10911-010-9169-x
[44]  Sexton T, Yaffe E, Kenigsberg E, Bantignies F, Leblanc B, et al. (2012) Three-dimensional folding and functional organization principles of the Drosophila genome. Cell 148: 458–472. doi: 10.1016/j.cell.2012.01.010
[45]  Gruenbaum Y, Hochstrasser M, Mathog D, Saumweber H, Agard DA, et al. (1984) Spatial organization of the Drosophila nucleus: a three-dimensional cytogenetic study. Journal of Cell Science Supplement 1: 223–234. doi: 10.1242/jcs.1984.supplement_1.14
[46]  Chiarle R, Voena C, Ambrogio C, Piva R, Inghirami G (2008) The anaplastic lymphoma kinase in the pathogenesis of cancer. Nature Reviews Cancer 8: 11–23. doi: 10.1038/nrc2291
[47]  Wijchers PJ, de Laat W (2011) Genome organization influences partner selection for chromosomal rearrangements. Trends in Genetics 27: 63–71. doi: 10.1016/j.tig.2010.11.001
[48]  Miné-Hattab J, Rothstein R (2012) Increased chromosome mobility facilitates homology search during recombination. Nature Cell Biology 14: 510–517. doi: 10.1038/ncb2472
[49]  Dion V, Kalck V, Horigome C, Towbin BD, Gasser SM (2012) Increased mobility of double-strand breaks requires Mec1, Rad9 and the homologous recombination machinery. Nature Cell Biology 14: 502–509. doi: 10.1038/ncb2465
[50]  Grossmann V, Kohlmann A, Klein H-U, Schindela S, Schnittger S, et al. (2011) Targeted next-generation sequencing detects point mutations, insertions, deletions and balanced chromosomal rearrangements as well as identifies novel leukemia-specific fusion genes in a single procedure. Leukemia 25: 671–680. doi: 10.1038/leu.2010.309
[51]  Sakarya O, Breu H, Radovich M, Chen Y, Wang YN, et al. (2012) RNA-Seq Mapping and Detection of Gene Fusions with a Suffix Array Algorithm. PLoS Computational Biology 8: e1002464. doi: 10.1371/journal.pcbi.1002464
[52]  Asmann YW, Necela BM, Kalari KR, Hossain A, Baker TR, et al. (2012) Detection of Redundant Fusion Transcripts as Biomarkers or Disease-Specific Therapeutic Targets in Breast Cancer. Cancer Research 72: 1921–1928. doi: 10.1158/0008-5472.can-11-3142
[53]  D？lken G, Illerhaus G, Hirt C, Mertelsmann R (1996) BCL-2/JH rearrangements in circulating B cells of healthy blood donors and patients with nonmalignant diseases. Journal of Clinical Oncology 14: 1333–1344.
[54]  Roth RB, Hevezi P, Lee J, Willhite D, Lechner SM, et al. (2006) Gene expression analyses reveal molecular relationships among 20 regions of the human CNS. Neurogenetics 7: 67–80. doi: 10.1007/s10048-006-0032-6
[55]  Wang X, Wei X, Thijssen B, Das J, Lipkin SM, et al. (2012) Three-dimensional reconstruction of protein networks provides insight into human genetic disease. Nature Biotechnology 30: 159–164. doi: 10.1038/nbt.2106
[56]  Burge S, Kelly E, Lonsdale D, Mutowo-Muellenet P, McAnulla C, et al. (2012) Manual GO annotation of predictive protein signatures: the InterPro approach to GO curation. Database 2012: bar068. doi: 10.1093/database/bar068
[57]  Engretiz JM, Agarwala V, Mirny LA (2012) Three-Dimensional Genome Architecture Influences Partner Selection for Chromosomal Translocations in Human Disease. PLoS ONE 7(9): e44196. doi: 10.1371/journal.pone.0044196

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