В-клетки

Клиническое и прогностическое значение молекулярных маркеров диффузной В-крупноклеточной лимфомы

ОБЗОРЫ , , , , , ,

С.М. Расторгуев1, Д.А. Королева2, Е.С. Булыгина1, С.В. Цыганкова1, Н.Г. Гончаров1, О.С. Нарайкин1, Н.Г. Габеева2, Е.Е. Звонков2, А.В. Недолужко1

1 ФГБУ «НИЦ “Курчатовский институт”», пл. Академика Курчатова, д. 1, Москва, Российская Федерация, 123182

2 ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4а, Москва, Российская Федерация, 125167

Для переписки: Артем Валерьевич Недолужко, канд. биол. наук, пл. Академика Курчатова, д. 1, Москва, Российская Федерация, 123182; тел.: +7(916)670-55-95; e-mail: nedoluzhko@gmail.com

Для цитирования: Расторгуев С.М., Королева Д.А., Булыгина Е.С. и др. Клиническое и прогностическое значение молекулярных маркеров диффузной В-крупноклеточной лимфомы. Клиническая онкогематология. 2019:12(1):95–100.

DOI: 10.21320/2500-2139-2019-12-1-95-100

РЕФЕРАТ

Диффузная В-крупноклеточная лимфома (ДВКЛ) — наиболее распространенная лимфатическая опухоль взрослых, она составляет примерно 30–40 % всех неходжкинских лимфом. К критериям диагноза относятся диффузный рост крупных анаплазированных опухолевых клеток, экспрессия В-клеточных маркеров и высокий индекс пролиферативной активности. Благодаря совершенствованию молекулярно-генетических технологий стало очевидно, что в основе клинического разнообразия лежит огромное количество генетических поломок, определяющих эпигенетическую модификацию экспрессии генов, вариабельность активации определенных сигнальных путей и иммунологические особенности опухолевых клеток. Исследование и систематизация молекулярных маркеров являются важным направлением в области диагностики и лечения ДВКЛ. В настоящем обзоре мы описываем данные о наиболее значимых молекулярных маркерах и современные представления об их клиническом значении.

Ключевые слова: лимфома, ДВКЛ, В-клетки, транскриптомика, экспрессия генов, эпигеномика, геномика.

Получено: 3 июля 2018 г.

Принято в печать: 10 декабря 2018 г.

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ЛИТЕРАТУРА

  1. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403(6769):503–11. doi: 10.1038/35000501.

  2. Rosenwald A, Alizadeh AA, Widhopf G, et al. Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. J Exp Med. 2001;194(11):1639–48. doi: 1084/jem.194.11.1639.

  3. Staudt LM, Dave S. The biology of human lymphoid malignancies revealed by gene expression profiling. Adv Immunol. 2005;87:163–208. doi: 10.1016/S0065-2776(05)87005-1.

  4. Звонков Е.Е., Морозова А.К., Кравченко С.К. и др. Восьмилетний опыт применения модифицированной программы NHL-BFM-90 в лечении взрослых больных первичной диффузной В-крупноклеточной лимфомой желудка. Гематология и трансфузиология. 2012;57(3):47–8.

    [Zvonkov EE, Morozova AK, Kravchenko SK, et al. Eight-year experience of using the modified NHL-BFM-90 program for treatment of adult patients with primary diffuse large B-cell gastric lymphoma. Gematologiya i transfuziologiya. 2012;57(3):47–8. (In Russ)]

  5. Магомедова А.У., Кравченко С.К., Кременецкая A.M. и др. Девятилетний опыт лечения больных диффузной В-крупноклеточной лимфосаркомой. Терапевтический архив. 2011;83(7):5–10.

    [Magomedova AU, Kravchenko SK, Kremenetskaya AM, et al. Nine-year experience in the treatment of patients with diffuse large B-cell lymphosarcoma. Terapevticheskii arkhiv. 2011;83(7):5–10. (In Russ)]

  6. Гаврилина О.А., Габеева Н.Г., Морозова А.К. и др. Роль высокодозной химиотерапии и трансплантации аутологичных стволовых клеток крови у пациентов с диффузной В-крупноклеточной лимфомой. Терапевтический архив. 2013;85(7):90–7.

    [Gavrilina OA, Gabeeva NG, Morozova AK, et al. Role of high-dose chemotherapy and autologous blood stem cell transplantation in patients with diffuse large B-cell lymphoma. Terapevticheskii arkhiv. 2013;85(7):90–7. (In Russ)]

  7. Габеева Н.Г., Королева Д.А., Беляева А.В. и др. Диффузная В-крупноклеточная лимфома с сочетанной реаранжировкой генов c-MYC и BCL6 с первичным поражением кожи: собственное наблюдение и обзор литературы. Терапевтический архив. 2017;89(7):85–92.

    [Gabeeva NG, Koroleva DA, Belyaeva AV, et al. Diffuse large B-cell lymphoma with concomitant c-MYC and BCL6 gene rearrangements with primary skin involvement: A case report and a review of literature. Terapevticheskii arkhiv. 2017;89(7):85–92. (In Russ)]

  8. Martelli M, Ferreri AJ, Agostinelli C, et al. Diffuse large B-cell lymphoma. Crit Rev Oncol Hematol. 2013;87(2):146–71. doi: 10.1016/j.critrevonc.2012.12.009.

  9. Cohen M, Vistarop AG, Huaman F, et al. Epstein-Barr virus lytic cycle involvement in diffuse large B cell lymphoma. Hematol Oncol. 2017;36(1):98–103. doi: 10.1002/hon.2465.

  10. Lenz G, Wright G, Dave SS, et al. Stromal gene signatures in large-B-cell lymphomas. N Engl J Med. 2008;359(22):2313–23. doi: 10.1056/NEJMoa0802885.

  11. Wright G, Tan B, Rosenwald A, et al. A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma. Proc Natl Acad Sci USA. 2003;100(17): 9991–6. doi: 10.1073/pnas.1732008100.

  12. Skryabin KG, Prokhortchouk EB, Mazur AM, et al. Combining Two Technologies for Full Genome Sequencing of Human. Acta Nat. 2009;1(3):102–7.

  13. Artemov AV, Boulygina ES, Tsygankova SV, et al. Study of Alzheimer Family Case Reveals Hemochromotosis-Associated HFE Mutation. Hum Gen Var. 2014;1(1):14004. doi: 10.1038/hgv.2014.4.

  14. Scelo G, Riazalhosseini Y, Greger L, et al. Variation in genomic landscape of clear cell renal cell carcinoma across Europe. Nat Commun. 2014;5(1):5135. doi: 10.1038/ncomms6135.

  15. Shipp MA, Ross KN, Tamayo P, et al. Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nat Med. 2002;8(1):68–74. doi: 10.1038/nm0102-68.

  16. Scherer F, Kurtz DM, Newman AM, et al. Distinct biological subtypes and patterns of genome evolution in lymphoma revealed by circulating tumor DNA. Sci Transl Med. 2016;8(364):364ra155. doi: 10.1126/scitranslmed.aai8545.

  17. Lawrie CH, Soneji S, Marafioti T, et al. MicroRNA expression distinguishes between germinal center B cell-like and activated B cell-like subtypes of diffuse large B cell lymphoma. Int J Cancer. 2007;121(5):1156–61. doi: 10.1002/ijc.22800.

  18. Malumbres R, Sarosiek KA, Cubedo E, et al. Differentiation stage–specific expression of microRNAs in B lymphocytes and diffuse large B-cell lymphomas. Blood. 2009;113(16):3754–64. doi: 10.1182/blood-2008-10-184077.

  19. Zhu D, Fang C, Li X, et al. Predictive analysis of long non-coding RNA expression profiles in diffuse large B-cell lymphoma. Oncotarget. 2017;8(14):23228–36. doi: 10.18632/oncotarget.15571.

  20. Peng W, Fan H, Wu G, et al. Upregulation of long noncoding RNA PEG10 associates with poor prognosis in diffuse large B cell lymphoma with facilitating tumorigenicity. Clin Exp Med. 2016;16(2):177–82. doi: 10.1007/s10238-015-0350-9.

  21. Peng W, Feng J. Long noncoding RNA LUNAR1 associates with cell proliferation and predicts a poor prognosis in diffuse large B-cell lymphoma. Biomed Pharmacother. 2016;77:65–71. doi: 10.1016/j.biopha.2015.12.001.

  22. Peng W, Wu J, Feng J. Long noncoding RNA HULC predicts poor clinical outcome and represents pro-oncogenic activity in diffuse large B-cell lymphoma. Biomed Pharmacother. 2016;79:188–93. doi: 10.1016/j.biopha.2016.02.032.

  23. Yan Y, Han J, Li Z, et al. Elevated RNA expression of long non-coding HOTAIR promotes cell proliferation and predicts a poor prognosis in patients with diffuse large B cell lymphoma. Mol Med Rep. 2016;13(6):5125–31. doi: 10.3892/mmr.2016.5190.

  24. Li L-J, Chai Y, Guo X-J, et al. The effects of the long non-coding RNA MALAT-1 regulated autophagy-related signaling pathway on chemotherapy resistance in diffuse large B-cell lymphoma. Biomed Pharmacother. 2017;89:939–48. doi: 10.1016/j.biopha.2017.02.011.

  25. Sun J, Cheng L, Shi H, et al. A potential panel of six-long non-coding RNA signature to improve survival prediction of diffuse large-B-cell lymphoma. Sci Rep. 2016;6(1):27842. doi: 10.1038/srep27842.

  26. Verma A, Jiang Y, Du W, et al. Transcriptome sequencing reveals thousands of novel long non-coding RNAs in B cell lymphoma. Gen Med. 2015;7(1):110. doi: 10.1186/s13073-015-0230-7.

  27. Gutierrez-Garcia G, Cardesa-Salzmann T, Climent F, et al. Gene-expression profiling and not immunophenotypic algorithms predicts prognosis in patients with diffuse large B-cell lymphoma treated with immunochemotherapy. Blood. 2011;117(18):4836–43. doi: 10.1182/blood-2010-12-322362.

  28. Schuetz JM, Johnson NA, Morin RD, et al. BCL2 mutations in diffuse large B-cell lymphoma. Leukemia. 2012;26(6):1383–90. doi: 10.1038/leu.2011.378.

  29. Greenough A, Moffitt A, Jima D, et al. Strand-Specific Total RNA Sequencing Establishes the Complete Transcriptome and Alternative Splicing Repertoire in Diffuse Large B Cell Lymphoma. Blood. 2014;124(21):864.

  30. Park HY, Lee SB, Yoo HY, et al. Whole-Exome and Transcriptome Sequencing of Refractory Diffuse Large B-Cell Lymphoma. Oncotarget. 2016;7(52): 86433–45. doi: 10.18632/oncotarget.13239.

  31. Dekker JD, Park D, Shaffer AL, et al. Subtype-Specific Addiction of the Activated B-Cell Subset of Diffuse Large B-Cell Lymphoma to FOXP1. Proc Natl Acad Sci USA. 2016;113(5):E577–86. doi: 10.1073/pnas.1524677113.

  32. Reddy A, Zhang J, Davis NS, et al. Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma. Cell. 2017;171(2):481–94.e15. doi: 10.1016/j.cell.2017.09.027.

  33. Saez AI, Saez AJ, Artiga MJ, et al. Building an outcome predictor model for diffuse large B-cell lymphoma. Am J Pathol. 2004;164(2):613–22. doi: 10.1016/S0002-9440(10)63150-1.

  34. Campo E. MYC in DLBCL: partners matter. Blood. 2015;126(22):2439–40. doi: 10.1182/blood-2015-10-671362.

  35. Schmitz R, Wright GW, Huang DW, et al. Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma. N Engl J Med. 2018;378(15):1396–407. doi: 10.1056/NEJMoa1801445.

  36. Dubois S, Viailly PJ, Mareschal S, et al. Next-generation sequencing in diffuse large B-cell lymphoma highlights molecular divergence and therapeutic opportunities: a LYSA study. Clin Cancer Res. 2016;22(12):2919–28. doi: 10.1158/1078-0432.CCR-15-2305.

  37. Lohr JG, Stojanov P, Lawrence MS, et al. Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc Natl Acad Sci USA. 2012;109(10):3879–84. doi: 10.1073/pnas.1121343109.

  38. Morin RD, Mungall K, Pleasance E, et al. Mutational and structural analysis of diffuse large B-cell lymphoma using whole-genome sequencing. Blood. 2013;122(7):1256–65. doi: 10.1182/blood-2013-02-483727.

  39. Pasqualucci L, Trifonov V, Fabbri G, et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nat Genet. 2011;43(9):830–7. doi: 10.1038/ng.892.

  40. Roschewski M, Dunleavy K, Pittaluga S, et al. Circulating tumour DNA and CT monitoring in patients with untreated diffuse large B-cell lymphoma: a correlative biomarker study. Lancet Oncol. 2015;16(5):541–9. doi: 10.1016/S1470-2045(15)70106-3.

  41. Yeh P, Hunter T, Sinha D, Ftouni S, et al. Circulating tumour DNA reflects treatment response and clonal evolution in chronic lymphocytic leukaemia. Nat Commun. 2017;8:14756. doi: 10.1038/ncomms14756.

  42. Khare D, Goldschmidt N, Bardugo A, et al. Plasma microRNA profiling: Exploring better biomarkers for lymphoma surveillance. PLoS One. 2017;12(11):e0187722. doi: 10.1371/journal.pone.0187722.

  43. Meng Y, Quan L, Liu A. Identification of key microRNAs associated with diffuse large B-cell lymphoma by analyzing serum microRNA expressions. Gene. 2018;642:205–11. doi: 10.1016/j.gene.2017.11.022.

  44. Kurtz DM, Green MR, Bratman SV, et al. Noninvasive Monitoring of Diffuse Large B-Cell Lymphoma by Immunoglobulin High-Throughput Sequencing. Blood. 2015;125(24):3679–87. doi: 10.1182/blood-2015-03-635169.

  45. Cohen JD, Li L, Wang Y, et al. Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science. 2018;359(6378):926–30. doi: 10.1126/science.aar3247.

  46. Shaknovich R, Melnick A. Epigenetics and B-Cell Lymphoma. Curr Opin Hematol. 2011;18(4):293–9. doi: 10.1097/MOH.0b013e32834788cf.

  47. Shaknovich R, Geng H, Johnson NA, et al. DNA methylation signatures define molecular subtypes of diffuse large B-cell lymphoma. Blood. 2010;116(20):e81–9. doi: 10.1182/blood-2010-05-285320.

  48. Lai AY, Fatemi M, Dhasarathy A, et al. DNA methylation prevents CTCF-mediated silencing of the oncogene BCL6 in B cell lymphomas. J Exp Med. 2010;207(9):1939–50. doi: 10.1084/jem.20100204.

  49. Kristensen LS, Hansen JW, Kristensen SS, et al. Aberrant Methylation of Cell-Free Circulating DNA in Plasma Predicts Poor Outcome in Diffuse Large B Cell Lymphoma. Clin Epigen. 2016;8(1):5. doi: 10.1186/s13148-016-0261-y.

  50. Wedge E, Hansen JW, Garde C, et al. Global hypomethylation is an independent prognostic factor in diffuse large B cell lymphoma. Am J Hematol. 2017;92(7):689–94. doi: 10.1002/ajh.24751.

  51. Krajnovic M, Jovanovic MP, Mihaljevic B, et al. Hypermethylation of p15 Gene in Diffuse – Large B‐Cell Lymphoma: Association with Less Aggressiveness of the Disease. Clin Transl Sci. 2014;7(5):384–90. doi: 10.1111/cts.12162.

  52. Chambwe N, Kormaksson M, Geng H, et al. Variability in DNA methylation defines novel epigenetic subgroups of DLBCL associated with different clinical outcomes. Blood. 2014;123(11):1699–708. doi: 10.1182/blood-2013-07-509885.

  53. Clozel T, Yang S, Elstrom RL, et al. Mechanism-based epigenetic chemosensitization therapy of diffuse large B-cell lymphoma. Cancer Discov. 2013;3(9):1002–19. doi: 10.1158/2159-8290.CD-13-0117.

  54. Pan H, Jiang Y, Boi M, et al. Epigenomic evolution in diffuse large B-cell lymphomas. Nat Commun. 2015;6(1):6921. doi: 10.1038/ncomms7921.

  55. Jing L, Su L, Ring BZ. Ethnic Background and Genetic Variation in the Evaluation of Cancer Risk: A Systematic Review. PLoS ONE. 2014;9(6):e97522. doi: 10.1371/journal.pone.0097522.

  56. Li Y, Wang Y, Wang Z, et al. Racial Differences in Three Major NHL Subtypes: Descriptive Epidemiology. Cancer Epidemiol. 2015;39(1):8–13. doi: 10.1016/j.canep.2014.12.001.