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Mutational, immune microenvironment, and clinicopathological profiles of diffuse large B-cell lymphoma and follicular lymphoma with BCL6 rearrangement

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Abstract

BCL6-rearrangement (BCL6-R) is associated with a favorable prognosis of follicular lymphoma (FL), but the mechanism is unknown. We analyzed the clinicopathological, immune microenvironment (immune checkpoint, immuno-oncology markers), and mutational profiles of 10 BCL6-R-positive FL, and 19 BCL6-R-positive diffuse large B-cell lymphoma (DLBCL) cases (both BCL2-R and MYC-R negative). A custom-made panel included 168 genes related to aggressive B-cell lymphomas and FL. FL cases were nodal, histological grade 3A in 70%, low Ki67; and had a favorable overall and progression-free survival. DLBCL cases were extranodal in 60%, IPI high in 63%, non-GCB in 60%, EBER-negative; and had a progression-free survival comparable to that of DLBCL NOS. The microenvironment had variable infiltration of M2-like tumor-associated macrophages (TAMs) that were CD163, CSF1R, LAIR1, PD-L1, and CD85A (LILRB3) positive; but had low IL10 and PTX3 expression. In comparison to FL, DLBCL had higher TAMs, IL10, and PTX3 expression. Both lymphoma subtypes shared a common mutational profile with mutations in relevant pathogenic genes such as KMT2D, OSBPL10, CREBBP, and HLA-B (related to chromatin remodeling, metabolism, epigenetic modification, and antigen presentation). FL cases were characterized by a higher frequency of mutations of ARID1B, ATM, CD36, RHOA, PLOD2, and PRPRD (p < 0.05). DLBCL cases were characterized by mutations of BTG2, and PIM1; and mutations of HIST1H1E and MFHAS1 to disease progression (p < 0.05). Interestingly, mutations of genes usually associated with poor prognosis, such as NOTCH1/2 and CDKN2A, were infrequent in both lymphoma subtypes. Some high-confidence variant calls were likely oncogenic, loss-of-function. MYD88 L265P gain-of-function was found in 32% of DLBCL. In conclusion, both BCL6-R-positive FL and BCL6-R-positive DLBCL had a common mutational profile; but also, differences. DLBCL cases had a higher density of microenvironment markers.

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Data availability

The NGS high-confidence calls data are available at the CERN Dada Centre (OpenAIRE, Zenodo): Carreras, Joaquim. (2023). High confidence calls (BCL6-R FL and DLBCL) (Version 1) [Data set]. Zenodo. https://doi.org/10.5281/zenodo.7765236.

For original data, please contact joaquim.carreras@tokai.ac.jp.

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Acknowledgements

We would like to acknowledge Masayuki Tanaka and Akinori Takase of the Bioinformatics section, Medical Science College Office, Tokai University, Japan, for their support in the bioinformatics analyses. The authors thank the technicians and scientists of the Genomics Core Facility of IDIBAPS for their assistance in performing the NGS analysis.

Funding

This research was funded by the Ministry of Education, Culture, Sports, Science and Technology (MEXT), grant numbers KAKEN 23K06454, 15K19061, 18K15100, and 24590430, and the Tokai University School of Medicine research incentive assistant plan (grant number 2021-B04). Rifat Hamoudi is funded by University of Sharjah grants (22010902103 and 24010902153).

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Authors and Affiliations

  1. Department of Pathology, School of Medicine, Tokai University, Tokyo, Japan

    Joaquim Carreras, Haruka Ikoma, Yara Yukie Kikuti, Masashi Miyaoka, Shinichiro Hiraiwa, Sakura Tomita, Yusuke Kondo, Atsushi Ito, Shunsuke Nagase, Hisanobu Miura & Naoya Nakamura

  2. Department of Hematology, School of Medicine, Tokai University, Tokyo, Japan

    Hiroshi Kawada

  3. Monoclonal Antibodies Core Unit, Spanish National Cancer Research Center (CNIO), Madrid, Spain

    Giovanna Roncador

  4. Department of Pathology, Esther Koplowitz Center (CEK), Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Hospital Clinic Barcelona, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain

    Elias Campo

  5. Research Institute for Medical and Health Science, Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates

    Rifat Hamoudi

  6. Division of Surgery and Interventional Science, University College London, London, UK

    Rifat Hamoudi

  7. BIMAI-Lab, Biomedically Informed Artificial Intelligence Laboratory, University of Sharjah, Sharjah, United Arab Emirates

    Rifat Hamoudi

Authors
  1. Joaquim Carreras
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  2. Haruka Ikoma
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  3. Yara Yukie Kikuti
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  4. Masashi Miyaoka
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  5. Shinichiro Hiraiwa
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  6. Sakura Tomita
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  7. Yusuke Kondo
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  8. Atsushi Ito
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  9. Shunsuke Nagase
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  10. Hisanobu Miura
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  11. Hiroshi Kawada
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  12. Giovanna Roncador
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  13. Elias Campo
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  14. Rifat Hamoudi
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  15. Naoya Nakamura
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Contributions

Conceptualization, N.N.; formal analysis, J.C.; investigation, J.C., Y.Y.K., M.M., S.H., S.T., H.I., Y.K., A.I., S.N., H.M., G.R., R.H., E.C. and N.N.; resources, N.N.; writing—original draft preparation, J.C.; writing—review and editing, J.C, N.N., E.C. and R.H.; supervision, N.N. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Joaquim Carreras.

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Declarations

This study was approved by the Institutional Review Board of Tokai University (IRB 151–21 and 14R080). This study complies with the WMA Declaration of Helsinki–Ethical Principles for Medical Research Involving Human Subjects.

Conflict of interest

No conflict of interest to declare.

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Key points

1- BCL6-rearrangement positive follicular and diffuse large B-cell lymphomas are special lymphoma subtypes.

2- Both subtypes had mutations of KMT2D, OSBPL10, CREBBP, and HLA-B that are related to chromatin remodeling, metabolism, and antigen presentation; but differences were also found.

Joaquim Carreras and Haruka Ikoma contributed equally to the project as the first authors.

Electronic supplementary material

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Supplementary file1 (PDF 1818 KB)

Appendix

Appendix

Table 5.

Table 6.

Table 5 General mutational landscape of BCL6 rearrangement-positive FL and DLBCL
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Table 6 Evaluation of the M2-like tumor-associated macrophages (TAMs) using immuno-oncology markers
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Carreras, J., Ikoma, H., Kikuti, Y.Y. et al. Mutational, immune microenvironment, and clinicopathological profiles of diffuse large B-cell lymphoma and follicular lymphoma with BCL6 rearrangement. Virchows Arch 484, 657–676 (2024). https://doi.org/10.1007/s00428-024-03774-z

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