Skip to main content

Advertisement

SpringerLink
Log in

Significant Role of Segmental Duplications and SIDD Sites in Chromosomal Translocations of Hematological Malignancies: A Multi-parametric Bioinformatic Analysis

  • Original Research Article
  • Published:
Interdisciplinary Sciences: Computational Life Sciences Aims and scope Submit manuscript

Abstract

Recurrent non-random chromosomal translocations are hallmark characteristics of leukemogenesis, and however, molecular mechanisms underlying these rearrangements are less explored. The fundamental question is, why and how chromosomes break and reunite so precisely in the genome. Meticulous understanding of mechanism leading to chromosomal rearrangement can be achieved by characterizing breakpoints. To address this hypothesis, a novel multi-parametric computational approach for characterization of major leukemic translocations within and around breakpoint region was performed. To best of our knowledge, this bioinformatic analysis is unique in finding the presence of segmental duplications (SDs) flanking breakpoints of all major leukemic translocation. Breakpoint islands (BpIs) were analyzed for stress-induced duplex destabilization (SIDD) sites along with other complex genomic architecture and physicochemical properties. Our study distinctly emphasizes on the probable correlative role of SDs, SIDD sites and various genomic features in the occurrence of breakpoints. Further, it also highlights potential features which may be playing a crucial role in causing double-strand breaks, leading to translocation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Brunstein CG, Dylla SJ, Verfaillie CM (2008) Chromosomal translocations in hematologic malignancies. Curr Genomics 3:313–334

    Article  Google Scholar 

  2. Fröhling Stefan, Döhner D (2008) Chromosomal abnormalities in cancer. N Engl J Med 359:722–734

    Article  PubMed  Google Scholar 

  3. Chetverina EV, Chetverin AB (2010) Nanocolonies and diagnostics of oncological diseases associated with chromosomal translocations. Biochemistry (Mosc) 75:1667–1691

    Article  CAS  Google Scholar 

  4. Hart SM, Foroni L (2002) Core binding factor genes and human leukemia. Haematologica 87:1307–1323

    PubMed  CAS  Google Scholar 

  5. Lam K, Zhang DE (2012) RUNX1 and RUNX1-ETO: roles in hematopoiesis and leukemogenesis. Front Biosci 17:1120–1139

    Article  CAS  PubMed Central  Google Scholar 

  6. Laurent E, Talpaz M, Kantarjian H (2001) The BCR gene and Philadelphia chromosome-positive leukemogenesis. Cancer Res 61:2343–2355

    PubMed  CAS  Google Scholar 

  7. Penserga ET, Skorski T (2007) Fusion tyrosine kinases: a result and cause of genomic instability. Oncogene 26:11–20

    Article  PubMed  CAS  Google Scholar 

  8. Peterson LF, Zhang DE (2004) The (8;21)translocation in leukemogenesis. Oncogene 23:4255–4262

    Article  PubMed  CAS  Google Scholar 

  9. Zelent A, Greaves M, Enver T (2004) Role of the TEL-AML1 fusion gene in the molecular pathogenesis of childhood acute lymphoblastic leukaemia. Oncogene 23:4275–4283

    Article  PubMed  CAS  Google Scholar 

  10. Zhang Y, Rowley JD (2006) Chromatin structural elements and chromosomal translocations in leukemia. DNA Repair (Amst) 5:1282–1297

    Article  CAS  Google Scholar 

  11. Chen Zhong (2006) Molecular cytogenetic markers related to prognosis in hematological malignancies. World J Pediatr 4:252–259

    Google Scholar 

  12. Albano F, Anelli L, Zagaria A (2010) Non-random distribution of genomic features in breakpoint regions involved in chronic myeloid leukemia cases with variant t(9,22) or additional chromosomal rearrangements. Mol Cancer 9:120

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  13. Albano F, Anelli L, Zagaria A (2010) Genomic segmental duplications on the basis of the t(9,22) rearrangement in chronic myeloid leukemia. Oncogene 29:2509–2516

    Article  PubMed  CAS  Google Scholar 

  14. Novo FJ, Vizmanos JL (2006) Chromosome translocations in cancer: computational evidence for the random generation of double-strand breaks. Trends Genet 22:193–196

    Article  PubMed  CAS  Google Scholar 

  15. Mitelman F, Johansson B, Mertens F (2004) Fusion genes and rearranged genes as a linear function of chromosome aberrations in cancer. Nat Genet 36:331–334

    Article  PubMed  CAS  Google Scholar 

  16. Francisco JN, Iñigo OM, José LV (2007) TICdb: a collection of gene-mapped translocation breakpoints in cancer. BMC Genom 8:33

    Article  CAS  Google Scholar 

  17. Karolchik D, Hinrichs AS, Kent WJ (2012). The UCSC Genome Browser. Curr Protoc Bioinf

  18. Merelli I, Guffanti A, Fabbri M (2010) RSSsite: a reference database and prediction tool for the identification of cryptic Recombination Signal Sequences in human and marine genomes. Nucleic Acids Res 38:W262–W267

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Bi C, Benham CJ (2004) WebSIDD: server for predicting stress-induced duplex destabilized (SIDD) sites in superhelical DNA. Bioinformatics 20:1477–1479

    Article  PubMed  CAS  Google Scholar 

  20. Friedel M, Nikolajewa S, Sühnel J (2009) DiProGB: the dinucleotide properties genome browser. Bioinformatics 25:2603–2604

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Nambiar M, Kari V, Raghavan SC (2008) Chromosomal translocations in cancer. Biochim Biophys Acta 1786:139–152

    PubMed  CAS  Google Scholar 

  22. Gasparini P, Sozzi G, Pierotti MA (2007) The role of chromosomal alterations in human cancer development. J Cell Biochem 102:320–331

    Article  PubMed  CAS  Google Scholar 

  23. Gilliland DG, Jordan CT, Felix CA (2004) The molecular basis of leukemia, optional hematology. Am Soc Hematol Educ Program 80–97

  24. Nambiar M, Raghavan SC (2011) How does DNA break during chromosomal translocations? Nucleic Acids Res 39:5813–5825

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. Aplan Peter D (2006) Causes of oncogenic chromosomal translocation. Trends Genet 22:46–55

    Article  PubMed  CAS  Google Scholar 

  26. Bacolla A, Wojciechowska M, Kosmider B, Larson JE, Wells RD (2006) The involvement of non-BDNA structures in gross chromosoma l rearrangements. DNA Repair (Amst) 5:1161–1170

    Article  CAS  Google Scholar 

  27. Raghavan SC, Lieber MR (2006) DNA structures at chromosomal translocation sites. BioEssays 28:480–494

    Article  PubMed  CAS  Google Scholar 

  28. Gollin SM (2007) Mechanisms leading to nonrandom, non-homologous chromosomal translocations in leukemia. Semin Cancer Biol 17:74–79

    Article  PubMed  CAS  Google Scholar 

  29. Ji Y, Eichler EE, Schwartz S, Nicholls RD (2000) Structure of chromosomal duplicons and their role in mediating human genomic disorders. Genome Res 10:597–610

    Article  PubMed  CAS  Google Scholar 

  30. Zagaria A, Anelli L, Coccaro N, Tota G et al (2014) 5′RUNX1-3′USP42 chimeric gene in acute myeloid leukemia can occur through an insertion mechanism rather than translocation and may be mediated by genomic segmental duplications. Mol Cytogenet 7:66

    Article  PubMed  PubMed Central  Google Scholar 

  31. Kolomietz E, Meyn MS, Pandita A (2002) The role of Alu repeat clusters as mediators of recurrent chromosomal aberrations in tumors. Genes Chromosomes Cancer 35:97–112

    Article  PubMed  CAS  Google Scholar 

  32. Wang H, Noordewier M, Benham CJ (2004) Stress-induced DNA duplex destabilization (SIDD) in the E. coli genome: SIDD sites are closely associated with promoters. Genome Res 14:1575–1584

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  33. Winkelmann S, Klar M, Benham C (2006) The positive aspects of stress: strain initiates domain decondensation (SIDD). Brief Funct Genomic Proteomic 5:24–31

    Article  PubMed  CAS  Google Scholar 

  34. Zhang M, Swanson PC (2008) V(D)J recombinase binding and cleavage of cryptic recombination signal sequences identified from lymphoid malignancies. J Biol Chem 283:6717–6727

    Article  PubMed  CAS  Google Scholar 

  35. Raghavan SC, Swanson PC, Ma Y, Lieber MR (2005) Double-strand break formation by the RAG complex at the bcl-2 major breakpoint region and at other non-B DNA structures in vitro. Mol Cell Biol 25:5904–5919

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  36. Dik WA, Nadel B, Przybylski GK (2007) Different chromosomal breakpoints impact the level of LMO2 expression in T-ALL. Blood 110:388–392

    Article  PubMed  CAS  Google Scholar 

  37. Kato T, Kurahashi H, Emanuel BS (2012) Chromosomal translocations and palindromic AT-rich repeats. Curr Opin Genet Dev 22:221–228

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. Edelmann L, Spiteri E, Koren K (2001) AT rich palindromes mediate the constitutional t(11;22) translocation. Am J Hum Genet 68:1–13

    Article  PubMed  CAS  Google Scholar 

  39. Kogo Hiroshi, Inagaki Hidehito, Ohye Tamae (2007) Cruciform extrusion propensity of human translocation-mediating palindromic AT-rich repeats. Nucleic Acids Res 35:1198–1208

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  40. Yakovchuk P, Protozanova E, Frank-Kamenetskii MD (2006) Base-stacking and base-pairing contributions into thermal stability of the DNA double helix. Nucleic Acids Res 34:564–574

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  41. Ferber MJ, Eilers P, Schuuring E (2004) Positioning of cervical carcinoma and Burkitt lymphoma translocation breakpoints with respect to the human papilloma virus integration cluster in FRA8C at 8q24.13. Cancer Genet Cytogenet 154:1–9

    Article  PubMed  CAS  Google Scholar 

  42. Morelli C, Karayianni E, Magnanini C (2002) Cloning and characterization of the common fragile site FRA6F harboring a replicative senescence gene and frequently deleted in human tumors. Oncogene 21:7266–7276

    Article  PubMed  CAS  Google Scholar 

  43. Ferguson DO, Alt FW (2001) DNA double strand break repair and chromosomal translocation: lessons from animal models. Oncogene 20:5572–5579

    Article  PubMed  CAS  Google Scholar 

  44. Van Gent DC, Hoeijmakers JH, Kanaar R (2001) Chromosomal stability and the DNA double-stranded break connection. Nat Rev Genet 2:196–206

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to acknowledge The Gujarat Cancer and Research Institute for providing administrative support. Among all author M.P. is thankful to Prof S.P.Bhatnagar, Head, Department of Physics, M.K Bhavnagar University for providing Computational Facility at Esteemed Department.

Author information

Author notes

    Authors and Affiliations

    1. Department of Microbiology, MVM Science College, Saurashtra University, Near Under Bridge, Kalawad Road, Rajkot, Gujarat, 360007, India

      Aditi Daga & Valentina Umrania

    2. Division of Medicinal Chemistry and Pharmacogenomics, Department of Cancer Biology, The Gujarat Cancer and Research Institute, NCH Campus, Asarwa, Ahmedabad, Gujarat, 380016, India

      Krupa Shah, Shanaya Patel & Rakesh Rawal

    3. BIT Virtual Institute of Bioinformatics (GCRI Node), GSBTM, Gandhinagar, Gujarat, India

      Afzal Ansari

    4. BIT Virtual Institute of Bioinformatics (GCRI Node), Division of Medicinal Chemistry and Pharmacogenomics, The Gujarat Cancer and Research Institute, NCH Campus, Asarwa, Ahmedabad, Gujarat, 380016, India

      Afzal Ansari

    5. Department of Bioinformatics, Maharaja Krishnakumarsinhji Bhavnagar University, Bhavnagar, Gujarat, 364022, India

      Medha Pandya

    6. Department of Physics, Maharaja Krishnakumarsinhji Bhavnagar University, Bhavnagar, Gujarat, 364022, India

      Medha Pandya

    Authors
    1. Aditi Daga
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Afzal Ansari
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Medha Pandya
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Krupa Shah
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Shanaya Patel
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Rakesh Rawal
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Valentina Umrania
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Rakesh Rawal.

    Ethics declarations

    Conflict of interest

    The authors declare that they have no conflict of interest.

    Additional information

    Aditi Daga and Afzal Ansari have contributed equally in this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary material 1 (DOCX 43 kb)

    12539_2016_203_MOESM2_ESM.tif

    Fig S1. Flow chart for retrieval of 1000 Base pair nucleotide sequences of fusion partners of major translocations from TICdb and UCSC tool. (TIFF 231 kb)

    Fig S2. Flowchart showing multiparametric computational analysis for known breakpoint region. (TIFF 280 kb)

    12539_2016_203_MOESM4_ESM.tif

    Fig. S3. Circos plot of various physico-chemical parameters at BpI for translocation t(4;11)A. Sequential/ systematic depiction of all the parameters at or near the breakpoint region that are scrutinized in our study. The outermost trail demarcates the BpI sequence of 1000 bps of chr 4(magenta) and 11(fluorescent Green) in clockwise direction. While the inner trails demarcate various parameters as mentioned: Intronic region(blue); TICdb fusion sequence(red); SIDD regions(orange); Repeats(turquoise blue); Recombination signal sequence region(RSS-pink); graphical representation of Flexibility(dark blue); Stability(red); Stacking Energy(purple);Percentage of AT content(yellow); name of genes and their locations are mentioned in innermost circle. Horizontal black line indicates the exact breakpoint location and the respective features present at that particular point of break. (TIFF 629 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Daga, A., Ansari, A., Pandya, M. et al. Significant Role of Segmental Duplications and SIDD Sites in Chromosomal Translocations of Hematological Malignancies: A Multi-parametric Bioinformatic Analysis. Interdiscip Sci Comput Life Sci 10, 467–475 (2018). https://doi.org/10.1007/s12539-016-0203-6

    Download citation

    • Received:

    • Revised:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12539-016-0203-6

    Keywords

    Search

    Navigation