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PD-L1/PD-L2 genetic profile in the molecular cytogenetic classification of classic Hodgkin lymphoma

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Abstract

Genomic imbalance at 9p24.1 locus, the chromosome region that maps PD-L1 and PD-L-2 (programmed death ligand 1 and 2) genes, is a recurrent alteration in classic Hodgkin lymphoma (cHL). We analyzed 9p24.1 imbalance by fluorescence in situ hybridization assay on formalin-fixed paraffin-embedded biopsies of 28 patients with newly diagnosed cHL to characterize the genetic profiles. Results were correlated with PD-L1 (H-score) and LMP-1 (latent membrane protein 1) protein expression of Epstein-Barr virus by immunohistochemistry and clinical features. Genomic alterations in Hodgkin/Reed Sternberg (H/RS) cells were classified as amplification, copy gain, and polysomy. Three molecular cytogenetic groups were defined according to the type and frequency of the copy number alteration: Group A (with amplification) 32%, Group G (with > 50% cells with copy gains but without amplification) 36%, and Group P (with ≥ 50% cells with polysomies but without amplification) 32%. A different frequency of copy gains (p = 0.02) and polysomies (p ≤ 0.01) among groups was found. A negative correlation between the percentage of H/RS cells with polysomies and the PD-L1 protein expression (p ≤ 0.01) was observed. Tumor microenvironmental cells showed chromosome 9 monosomy particularly associated to Group P. The highest H-score mean value was observed in Group A (265.6), while Groups G and P showed 123 and 60.3 H-score, respectively. Group P showed the highest mean age (p = 0.036) and increased frequency of advanced stages, B symptoms, and extranodal involvement, while Groups A and G were associated with localized stages (p = 0.035) and bulky mass, highlighting the importance of 9p24.1 genomic imbalance profile in the biological characterization of cHL.

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Data availability

The datasets generated during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors thanks Bioars Laboratory due to its collaboration with part of the ZytoVision FISH probes used in the present study.

Funding

This work was supported by grants from the Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT) (PICT N°: 2014–1566), CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas) (PID N° 1122015 0100753), “Alberto J. Roemmers” Foundation and the Master in Medical Molecular Biology, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Argentina.

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Authors and Affiliations

  1. Laboratorio de Genética de Neoplasias Linfoides, Instituto de Medicina Experimental, CONICET-Academia Nacional de Medicina, J.A. Pacheco de Melo 3081, C1425AUM, Buenos Aires, Argentina

    Mauro García-Montenegro & Irma Slavutsky

  2. Servicio de Patología, Instituto de Investigaciones Hematológicas “Mariano R. Castex”, Academia Nacional de Medicina, Buenos Aires, Argentina

    Marina Narbaitz & María Fernanda Metrebian

  3. Servicio de Patología, Fundaleu, Buenos Aires, Argentina

    Marina Narbaitz

  4. Servicio de Hematología, Fundaleu, Buenos Aires, Argentina

    Astrid Pavlovsky

  5. Centro de Hematología Pavlovsky, Buenos Aires, Argentina

    Astrid Pavlovsky

Authors
  1. Mauro García-Montenegro
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  2. Marina Narbaitz
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  3. María Fernanda Metrebian
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  4. Astrid Pavlovsky
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  5. Irma Slavutsky
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Contributions

All authors contributed to the study’s conception and design. MGM was responsible for methodology, data acquisition, analysis, and interpretation of results. MN and MFM contributed to the anatomic-pathologic diagnosis. AP was responsible for clinical data collection and follow-up of patients and collaborated with the writing of the manuscript. MGM and IS were responsible for the study conceptualization, writing the first draft of the manuscript, and reviewing and editing the final version. All authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Mauro García-Montenegro.

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The study was approved by the Ethics Committees of each Institution, and it is in accordance with the current version of the Helsinki Declaration.

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All patients provided their written informed consent.

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The authors declare no competing interests.

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García-Montenegro, M., Narbaitz, M., Metrebian, M.F. et al. PD-L1/PD-L2 genetic profile in the molecular cytogenetic classification of classic Hodgkin lymphoma. Virchows Arch (2025). https://doi.org/10.1007/s00428-025-04047-z

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