Resumo
Introducción: el linfoma de Hodgkin clásico presenta escasas células de Reed Sternberg/Hodgkin inmersas en un abundante microambiente tumoral. Los desbalances genómicos del locus 9p24.1 han sido asociados con alteraciones en la expresión de los genes del ligando de muerte celular 1 y 2, ambos reguladores de la respuesta inmune. Objetivo: evaluar desbalances genómicos del locus 9p24.1 en células de Reed Sternberg/Hodgkin y del microambiente tumoral en biopsias de pacientes con linfoma d Hodgkin clásico y correlacionarlo con la expresión del ligando de muerte celular 1 y la presentación de la enfermedad. Materiales y Métodos: se efectuó hibridación in situ en biopsias de 22 pacientes con linfoma de Hodgkin clásico dirigida a los genes del ligando de muerte celular 1 y 2. Las alteraciones se clasificaron en: amplificación, ganancia y polisomía. La expresión se evaluó mediante inmunohistoquímica. Resultados: todos los pacientes mostraron alteraciones del número de copias. Se diferenciaron dos grupos: con amplificación (32 %) y sin amplificación (68 %); este último subdividido en: rico en ganancia (53 %) y rico en polisomías (47 %). El grupo rico en polisomías mostró mayor edad (p=0,027). El 40 % de los pacientes con amplificación y rico en ganancias no presentó masa bulky. La expresión proteica mostró score +3 sólo en estos últimos. El 100 % de los casos ricos en polisomías presentaron monosomía del cromosoma 9 en los linfocitos circundantes respecto al 36,4 % de los otros dos grupos. Conclusiones: Nuestros datos constituyen un aporte a la caracterización biológica del LHC, de interés en el marco de las nuevas modalidades terapéuticas.
Referências
Shanbhag S, Ambinder RF. Hodgkin Lymphoma: A review and update on recent progress. CA Cancer J Clin. 2018;68(2):116-32. PubMed PMID: 29194581; PubMed Central PMCID: PMC5842098.
Pavlovsky A, Fernandez I, Kurgansky N, Prates V, Zoppegno L, Negri P, et al. PET-adapted therapy after three cycles of ABVD for all stages of Hodgkin lymphoma: results of the GATLA LH-05 trial. Br J Haematol. 2019;185(5):865-73. PubMed PMID: 30864146.
Ferlay J, Soerjomataram I, Ervik M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5): E359-86. PubMed PMID: 25220842.
Kusminsky G, Abriata G, Forman D, et al. Hodgkin lymphoma burden in Central and South America. Cancer Epidemiol. 2016;44 Suppl 1:S158-67. PubMed PMID: 27678318.
Siegel RL Miller KD, Jemal A. Cancer Statistics, 2019. CA Cancer J Clin. 2019;69(1):7-34. PubMed PMID: 30620402.
Jaffe ES, Stein H, Swerdlow SH. Classic Hodgkin lymphoma. In: Swerdlow SH, Campo E, Harris NL, editors. WHO Classification
of Tumors of Hematopoietic and Lymphoid Tissues. Revised 4th ed. Lyon: IARC Press; 2017. p. 435-42.
Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016; 127(20):2375-90.
Hodgkin T. On some morbid appearances of the absorbent glands and spleen. Med. Chir. Trans. 1832;17:68-114
Mani H, Jaffe ES. Hodgkin lymphoma: an update on its biology with new insights into classification. Clin Lymph Res. 2009;9(3):206-16.
Küppers R. The biology of Hodgkin’s lymphoma. Nat Rev Cancer. 2009;9(1):15-27.
Younes A, Santoro A, Shipp M, Zinzani PL, Timmerman JM, Ansell S, et al. Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. The Lancet Oncol. 2016;17(9):1283-94.
Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372:311-9.
Liu Y, Sattarzadeh A, Diepstra A, Visser L, van den Berg A. The microenvironment in classical Hodgkin lymphoma: an actively shaped and essential tumor component. Semin Cancer Biol. 2014;24:15-22.
Aldinucci D, Celegato M, Casagrande N. Microenvironmental interactions in classical Hodgkin lymphoma and their role in promoting tumor growth, immune escape and drug resistance. Cancer Lett. 2016;380(1):243-52.
Calabretta E, d’Amore F, Carlo-Stella C. Immune and inflammatory cells of the tumor microenvironment represent novel therapeutic targets in classical Hodgkin lymphoma. Int J Mol Sci. 2019;20(21):5503.
Hartmann S, Martin-Subero JI, Gesk S, Husken J, Giefing M, Nagel I, et al. Detection of genomic imbalances in microdissected Hodgkin and Reed-Sternberg cells of classical Hodgkin’s lymphoma by array-based comparative genomic hybridization. Haematologica. 2008;93(9):1318-26.
Steidl C, Telenius A, Shah SP, Farinha P, Barclay L, Boyle M, et al. Genome-wide copy number analysis of Hodgkin Reed- Sternberg cells identifies recurrent imbalances with correlations to treatment outcome. Blood. 2010;116(3):418-27.
Cuceu C, Hempel WM, Sabatier L, Bosq J, Carde P, M’Kacher R. Chromosomal instability in Hodgkin lymphoma: An in-depth review and perspectives. Cancers. 2018;10(4):91.
Erdkamp FL, Schouten HC, Breed WP, Janssen WC, Hoffmann JJ, Schutte B, et al. DNA aneuploidy in Hodgkin’s disease: a multiparameter flow cytometric analysis. Leuk Lymphoma. 1994;12 (3-4):297-306.
Jansen MP, Hopman AH, Haesevoets AM, Gennotte IA, Bot FJ, Arends JW, et al. Chromosomal abnormalities in Hodgkin’s disease are not restricted to Hodgkin/Reed-Sternberg cells. J Pathol. 1998;185(2):145-52.
Green MR, Monti S, Rodig SJ, Juszczynski P, Currie T, O’Donnell E, et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary
mediastinal large B-cell lymphoma. Blood. 2010;116(17):3268- 77.
Roemer MG, Advani RH, Ligon AH, Natkunam Y, Redd RA, Homer H, et al. PD-L1 and PD-L2 Genetic Alterations Define Classical Hodgkin Lymphoma and Predict Outcome. J Clin Oncol. 2016;34(23):2690-7.
Joos S, Kupper M, Ohl S, von Bonin F, Mechtersheimer G, Bentz M, et al. Genomic imbalances including amplification of the tyrosine kinase gene JAK2 in CD30+ Hodgkin cells. Cancer Res. 2000;60(3):549-52.
Rui L, Emre NC, Kruhlak MJ, Chung HJ, Steidl C, Slack G, et al. Cooperative epigenetic modulation by cancer amplicon genes. Cancer Cell. 2010;18(6):590-605.
Schmitz R, Hansmann ML, Bohle V, Martin-Subero JI, Hartmann S, Mechtersheimer G, et al. TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma. J Exp Med. 2009;206(5):981-9.
Lake A, Shield LA, Cordano P, Chui DTY, Osborne J, Crae S, et al. Mutations of NFKBIA, encoding IkBa, are a recurrent finding in classical Hodgkin lymphoma but are not a unifying feature of non-EBV-associated cases. Int J Cancer. 2009;125(6):1334-42.
Emmerich F, Theurich S, Hummel M, Haeffker A, Vry MS, Döhner K, et al. Inactivating I kappa B epsilon mutations in Hodgkin/Reed-Sternberg cells. J Pathol. 2003;201(3):413-20.
Tiacci E, Penson A, Schiavoni G, Ladewig E, Fortini E, Wang Y, et al. New Recurrently Mutated Genes in Classical Hodgkin Lymphoma Revealed by Whole-Exome Sequencing of Microdissected Tumor Cells. Blood. 2016;128(22):1088.
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and Its Ligand in Tolerance and Immunity. Annu Rev Immunol. 2008;26(1):677-704.
Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of the PD 1 Immunoinhibitory Receptor by a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte Activation. J Exp Med. 2000;192(7):1027-34.
Konishi J, Yamazaki K, Azuma M, Kinoshita I, Dosaka-Akita H, Nishimura M. B7-H1 Expression on Non-Small Cell Lung Cancer Cells and Its Relationship with Tumor-Infiltrating Lymphocytes and Their PD-1 Expression. Clin Cancer Res. 2004;10(15):5094-100.
Thompson RH, Gillett MD, Cheville JC, Lohse CM, Dong H, Scott Webster W, et al. Costimulatory B7-H1 in renal cell carcinoma
subjects: Indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci USA. 2004;101(49):17174-9.
Ohigashi Y, Sho M, Yamada Y, Tsurui Y, Hamada K, Ikeda N, et al. Clinical Significance of Programmed Death-1 Ligand-1 and Programmed Death-1 Ligand-2 Expression in Human Esophageal Cancer. Clin. Cancer Res. 2005;11(8):2947-53.
Hino R, Kabashima K, Kato Y, Yagi H, Nakamura M, Honjo T, et al. Tumor Cell Expression of Programmed Cell Death-1
ligand 1 Is a Prognostic Factor for Malignant Melanoma. Cancer. 2010;116(7):1757-66.
Roosbroeck KV, Ferreiro JF, Tousseyn T, van der Krogt J-A, Michaux L, Pienkowska-Grela B, et al. Genomic Alterations of the JAK2 and PDL Loci Occur in a Broad Spectrum of Lymphoid Malignancies. Genes Chromosom Cancer. 2016;55(5):428-41.
Chapuy B, Roemer MGM, Stewart C, Tan Y, Abo RP, Zhang L, et al. Targetable genetic features of primary testicular and primary central nervous system lymphomas. Blood. 2016;127(7):869-81.
Cheng Z, Dai Y, Wang J, Shi J, Ke X, Fu L. High PD-L1 expression predicts poor prognosis in diffuse large B-cell lymphoma. Ann Hematol. 2018;97(6):1085-8.
Garaicoa FH, Roisman A, Arias M, Trila C, Fridmanis M, Abeldaño A, et al. Genomic imbalances and microRNA transcriptional profiles in patients with mycosis fungoides. Tumor Biol. 2016;37(10):13637-47.
Kinch A, Sundström C, Baecklund E, Backlin C, Daniel M, Enblad G. Expression of PD-1, PD-L1, and PD-L2 in posttransplant lymphoproliferative disorder after solid organ transplantation. Leuk Lymphoma. 2019;60(2):376-84.
Chen BJ, Chapuy B, Ouyang J, Sun HH, Roemer MGM, Xu ML, et al. PD-L1 Expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res. 2013;19(13):3462-73
Paydas S, Bağır E, Seydaoglu G, Ercolak V, Ergin M. Programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and EBVencoded RNA (EBER) expression in Hodgkin lymphoma. Ann Hematol 2015;94(9):1545-52.
Meignan M, Gallamini A, Haioun C. Report on the First International Workshop on interim-PET-scan in lymphoma. Leuk Lymphoma. 2009;50(8):1257-60.
Menter T, Bodmer-Haecki A, Dirnhofer S, Tzankov A. Evaluation of the diagnostic and prognostic value of PDL1 expression in Hodgkin and B-cell lymphomas. Hum Pathol. 2016;54:17-24.
Koh YW, Jeon YK, Yoon DH, Suh C, Huh J. Programmed death 1 expression in the peritumoral microenvironment is associated
with a poorer prognosis in classical Hodgkin lymphoma. Tumor Biol. 2016;37(6):7507-14.
Hollander P, Kamper P, Ekstrom Smedby K, Enblad G, Ludvigsen M, Mortensen J, et al. High proportions of PD-1 + and PD-L1 + leukocytes in classical Hodgkin lymphoma microenvironment are associated with inferior outcome. Blood Adv. 2017;1(18):1427-39.
Carey CD, Gusenleitner D, Lipschitz M, Roemer MGM, Stack EC, Gjini E, et al. Topological analysis reveals a PD-L1-associated microenvironmental niche for Reed-Sternberg cells in Hodgkin lymphoma. Blood. 2017;130(22):2420-30.
Falzetti D, Crescenzi B, Matteuci C, Falini B, Martelli MF, Van Den Berghe H, et al. Genomic instability and recurrent breakpoints are
main cytogenetic findings in Hodgkin’s disease. Haematologica. 1999;84(4):298-305.
M’Kacher R, Girinsky T, Koscielny S, Dossou J, Violot D, Beron-Gaillard N, et al. Baseline and treatment-induced chromosomal abnormalities in peripheral blood lymphocytes of Hodgkin’s lymphoma patients. Int J Radiat. Oncol Biol Phys.
;57(2):321-6.
Barrios L, Caballin MR, Miro R, Fuster C, Berrozpe G, Subias A, et al. Chromosome abnormalities in peripheral blood lymphocytes
from untreated Hodgkin’s patients. A possible evidence for chromosome instability. Hum Genet. 1988;78(4):320-4.
Salas C, Niembro A, Lozano V, Gallardo E, Molina B, Sanchez S, et al. Persistent genomic instability in peripheral blood lymphocytes from Hodgkin lymphoma survivors. Environ. Mol. Mutagen. 2012;53(4):271-80.
Mata E, Díaz-López A, Martín-Moreno AM, Sánchez-Beato M, Varela I, Mestre MJ, et al. Analysis of the mutational landscape of classic Hodgkin lymphoma identifies disease heterogeneity and potential therapeutic targets. Oncotarget. 2017;8(67):111386-95.
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