Evaluation of Heterozygosity Loss in STR-Loci of Tumor DNA in Multiple Myeloma Patients with Plasmacytoma Based on the Molecular Analysis of Complex Archival Tumor Samples

AUTOIMMUNE THROMBOCYTOPENIA ,

EE Nikulina1, MV Firsova1, NV Risinskaya1, YaA Kozhevnikova2, MV Solov’ev1, TV Abramova1, TN Obukhova1, AM Kovrigina1, AB Sudarikov1, LP Mendeleeva1

1 National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

2 Faculty of Fundamental Medicine, MV Lomonosov Moscow State University, 27-1 Lomonosovskii pr-t, Moscow, Russian Federation, 119192

For correspondence: Elena Evgen’evna Nikulina, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; e-mail: lenysh2007@rambler.ru

For citation: Nikulina EE, Firsova MV, Risinskaya NV, et al. Evaluation of Heterozygosity Loss in STR-Loci of Tumor DNA in Multiple Myeloma Patients with Plasmacytoma Based on the Molecular Analysis of Complex Archival Tumor Samples. Clinical oncohematology. 2022;15(2):156–66. (In Russ).

DOI: 10.21320/2500-2139-2022-15-2-156-166

ABSTRACT

Background. Multiple myeloma (MM) is a hematological malignancy with plasma cells as substrate. Sometimes MM is characterized by plasmacytomas, i.e., intra- and extraosseous tumors. A paraffin block containing plasmacytoma substrate provides valuable material to be used for analyzing the molecular biological characteristics of tumor. STR-profiling is a method for simultaneous evaluation of DNA degradation and integral assessment of tumor genome stability.

Aim. To describe STR-profiles of plasmacytoma DNA isolated from archival samples and to assess the integral stability of tumor genome against control DNA of patients.

Materials & Methods. The retrospective study enrolled 10 MM patients with plasmacytoma (7 women and 3 men) aged 34–62 years (median 53.5 years) who were treated at the National Research Center for Hematology from 2013 to 2021. Paired tumor/control DNA samples were obtained from all 10 patients.

Results. The present paper takes the first step in attempting a large-scale molecular genetic study of MM and provides first findings on the loss of heterozygosity (LOH) in plasmacytoma genome. All 10 patients showed LOH variants with different allelic loads having either deletion/quantitatively neutral LOH or duplication of one of the two alleles and involving 1–8 STR-loci. In plasmacytoma substrate the number of loci with LOH tended to be higher in the group with MM relapses compared with plasmacytomas identified at disease onset. According to the data analysis, LOH was frequently (in 4 out of 10 cases) detected on chromosomes 1 (1q42), 6 (6q14), 7 (7q21.11), 13 (13q31.1), and 21 (21q21.1).

Conclusion. The present paper shows the effectiveness of molecular analysis of DNAs being isolated from complex archival material consisting of paraffin blocks with plasmacytomas.

Keywords: multiple myeloma, plasmacytoma, loss of heterozygosity, STR-profiling.

Received: October 25, 2021

Accepted: January 28, 2022

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REFERENCES

  1. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538–е548. doi: 10.1016/S1470-2045(14)70442-5.
  2. Rosinol L, Beksac M, Zamagni E, et al. Expert review on soft-tissue plasmacytomas in multiple myeloma: definition, disease assessment and treatment considerations. Br J Haematol. 2021;194(3):496–507. doi: 10.1111/bjh.17338.
  3. Blade J, de Larrea FC, Rosinol L, et al. Soft-tissue plasmacytomas in multiple myeloma: incidence, mechanisms of extramedullary spread, and treatment approach. J Clin Oncol. 2011;29(28):3805–12. doi: 10.1200/JCO.2011.34.9290.
  4. Weinstock M, Ghobrial IM. Extramedullary multiple myeloma. Leuk Lymphoma. 2013;54(6):1135–41. doi: 10.3109/10428194.2012.740562.
  5. Mitsiades CS, McMillin DW, Klippel S, et al. The role of the bone marrow microenvironment in the pathophysiology of myeloma and its significance in the development of more effective therapies. Hematol Oncol Clin North Am. 2007;21(6):1007–34. doi: 10.1016/j.hoc.2007.08.007.
  6. Vande Broek I, Vanderkerken K, Van Camp B, Van Riet I. Extravasation and homing mechanisms in multiple myeloma. Clin Exp Metastasis. 2008;25(4):325–34. doi: 10.1007/s10585-007-9108-4.
  7. Dahl IM, Rasmussen T, Kauric G, Husebekk A. Differential expression of CD56 and CD44 in the evolution of extramedullary myeloma. Br J Haematol. 2002;116(2):273–7. doi: 10.1046/j.1365-2141.2002.03258.x.
  8. Фирсова М.В., Менделеева Л.П., Ковригина А.М. и др. Экспрессия молекулы адгезии CD56 на опухолевых плазматических клетках в костном мозге как фактор прогноза при множественной миеломе. Клиническая онкогематология. 2019;12(4):377–84. doi: 10.21320/2500-2139-2019-12-4-377-384.
    [Firsova MV, Mendeleeva LP, Kovrigina AM, et al. Expression of Adhesion Molecule CD56 in Tumor Plasma Cells in Bone Marrow as a Prognostic Factor in Multiple Myeloma. Clinical oncohematology. 2019;12(4):377–84. doi: 10.21320/2500-2139-2019-12-4-377-384. (In Russ)]
  9. Paydas S, Zorludemir S, Baslamisli F, et al. Vascular endothelial growth factor (VEGF) expression in plasmacytoma. Leuk Lymphoma. 2002;43(1):139–43. doi: 10.1080/10428190210203.
  10. Rasche L, Chavan SS, Stephens OW, et al. Spatial genomic heterogeneity in multiple myeloma revealed by multi-region sequencing. Nat Commun. 2017;8(1):1–11. doi: 10.1038/s41467-017-00296-y.
  11. Weinstock M, Aljawai Y, Morgan EA, et al. Incidence and clinical features of extramedullary multiple myeloma in patients who underwent stem cell transplantation. Br J Haematol. 2015;169(6):851–8. doi: 10.1111/bjh.13383.
  12. Firsova MV, Mendeleeva LP, Kovrigina AM, et al. Plasmacytoma in patients with multiple myeloma: morphology and immunohistochemistry. BMC Cancer. 2020;20(1):346. doi: 10.1186/s12885-020-06870-w.
  13. Beroukhim R, Mermel CH, Porter D, et al. The landscape of somatic copy-number alteration across human cancers. Nature. 2010;463(7283):899–905. doi: 10.1038/nature08822.
  14. Sidorova JV, Biderman BV, Nikulina EE, Sudarikov AB. A simple and efficient method for DNA extraction from skin and paraffin-embedded tissues applicable to T-cell clonality assays. Exp Dermatol. 2012;21(1):57–60. doi: 10.1111/j.1600-0625.2011.01375.x.
  15. Григорук О.Г., Пупкова Е.Э., Базулина Л.М., Лазарев А.Ф. Проведение молекулярно-генетических исследований с использованием ДНК клеток опухоли, полученных из цитологических препаратов. Лабораторная служба. 2017;6(1):23–8. doi: 10.17116/labs20176123-28.
    [Grigoruk OG, Pupkova EE, Bazulina LM, Lazarev AF. The execution of molecular genetic tests using DNA of tumor cells obtained from cytologic preparations. Laboratory Service. 2017;6(1):23–8. doi: 10.17116/labs20176123-28. (In Russ)]
  16. Сидорова Ю.В., Сорокина Т.В., Бидерман Б.В. и др. Определение минимальной остаточной болезни у больных В-клеточным хроническим лимфолейкозом методом пациент-специфичной ПЦР. Клиническая лабораторная диагностика. 2011;12:22–35.
    [Sidorova YuV, Sorokina TV, Biderman BV, et al. Minimal residual disease detection in patients with B-cell chronic lymphocytic leukemia by patient-specific PCR. Klinicheskaya laboratornaya diagnostika. 2011;12:22–35. (In Russ)]
  17. Вязовская Н.С., Русинова Г.Г., Азизова Т.В. и др. Возможность выделения ДНК из архивных тканей, полученных при аутопсии, для молекулярно-генетических исследований. Архив патологии. 2014;76(2):46–7.
    [Vyazovskaya NS, Rusinova GG, Azizova TV, et al. Possibility of DNA isolation from archived autopsy tissues for molecular genetic studies. Arkhiv patologii. 2014;76(2):46–7. (In Russ)]
  18. Ваганова А.Н. Гистотехнические решения для повышения качества препаратов нуклеиновых кислот, выделенных из парафиновых блоков. Гены и клетки. 2014;9(2):96–101.
    [Vaganova AN. Histotechnical solutions for quality improvement of nucleic acid specimens isolated from paraffin blocks. Geny i kletki. 2014;9(2):96–101. (In Russ)]
  19. Gouveia GR, Ferreira SC, Ferreira JE, et al. Comparison of two methods of RNA extraction from formalin-fixed paraffin-embedded tissue specimens. Biomed Res Int. 2014;2014:151724. doi: 10.1155/2014/151724.
  20. Liu Y, Jelloul F, Zhang Y, et al. Genetic Basis of Extramedullary Plasmablastic Transformation of Multiple Myeloma. Am J Surg Pathol. 2020;44(6):838–48. doi: 10.1097/PAS.0000000000001459.
  21. Chapman MA, Lawrence MS, Keats JJ, et al. Initial genome sequencing and analysis of multiple myeloma. Nature. 2011;471(7339):467–72. doi: 10.1038/nature09837.
  22. Lohr JG, Stojanov P, Carter SL, et al. Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy. Cancer Cell. 2014;25(1):91–101. doi: 10.1016/j.ccr.2013.12.015.
  23. Rasmussen T, Kuehl M, Lodahl M, et al. Possible roles for activating RAS mutations in the MGUS to MM transition and in the intramedullary to extramedullary transition in some plasma cell tumors. Blood. 2005;105(1):317–23. doi: 10.1182/blood-2004-03-0833.
  24. Hu Y, Chen W, Wang J. Progress in the identification of gene mutations involved in multiple myeloma. Onco Targets Ther. 2019;12:4075–80. doi: 10.2147/OTT.S205922.
  25. Broderick P, Chubb D, Johnson DC, et al. Common variation at 3p22.1 and 7p15.3 influences multiple myeloma risk. Nat Genet. 2011;44(1):58–61. doi: 10.1038/ng.993.
  26. Barwick BG, Gupta VA, Vertino PM, Boise LH. Cell of Origin and Genetic Alterations in the Pathogenesis of Multiple Myeloma. Front Immunol. 2019;10:1121. doi: 10.3389/fimmu.2019.01121.
  27. Walker BA, Leone PE, Jenner MW, et al. Integration of global SNP-based mapping and expression arrays reveals key regions, mechanisms, and genes important in the pathogenesis of multiple myeloma. Blood. 2006;108(5):1733–43. doi: 10.1182/blood-2006-02-005496.
  28. Pawlyn C, Loehr A, Ashby C, et al. Loss of heterozygosity as a marker of homologous repair deficiency in multiple myeloma: a role for PARP inhibition? Leukemia. 2018;32(7):1561–6. doi: 10.1038/s41375-018-0017-0.
  29. Kim M, Lee SH, Kim J, et al. Copy number variations could predict the outcome of bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. Genes Chromosomes Cancer. 2015;54(1):20–7. doi: 10.1002/gcc.22213.