Molecular Genetic Characteristics and Pathogenetic Mechanisms of Mantle Cell Lymphoma: A Cohort Study



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Abstract

BACKGROUND: In addition to the characteristic t(11;14) translocation, the genome of mantle cell lymphoma is distinguished by numerous secondary chromosomal aberrations and molecular genetic alterations.

AIM: This study aimed to assess the mutational profile of mantle cell lymphoma, identify the most frequent genetic aberrations, and determine their impact on overall survival.

METHODS: Twenty-four patients with classical stage III–IV mantle cell lymphoma were included. All patients underwent conventional cytogenetic analysis, fluorescence in situ hybridization, and next-generation sequencing. Karyotypes were interpreted in accordance with the International System for Human Cytogenomic Nomenclature (ISCN). Moreover, survival functions were estimated using the Kaplan–Meier method with the log-rank test. The relationship between survival time and independent variables was evaluated using univariate and multivariate Cox regression analyses.

RESULTS: Conventional cytogenetic analysis determined a normal karyotype in 19 (79.2%) patients. The t(11;14) translocation was detected in three patients, 17p deletion in two (8%), and a complex karyotype in two (8%). Fluorescence in situ hybridization analysis identified t(11;14) translocation in 16 (67%) patients, TP53/17p13 deletion in 4 (17%), and MYC/8q24 rearrangement in 3 (12.5%). TP53/17p13 deletion induced an independent negative effect on overall survival (p = 0.020). NGS revealed the most frequent mutations in ATM (36%), RYR1 (27%), BCR (27%), and KMT2D (23%) genes. Significant associations were observed between FAT1 and BCR (p = 0.013), MGA and KMT2D (p = 0.024), and DNMT3A and KMT2D (p = 0.043) mutations. Among the detected variants, the ATM mutation predicted poor overall survival; however, its statistical significance was lost after adjusting for TP53/17p13 deletion (p = 0.099).

CONCLUSION: Analysis of the mutational profile revealed the most frequent aberrations—mutations in ATM, BCR, and KMT2D genes—in mantle cell lymphoma, which potentially contribute to the tumor’s pathogenesis.

About the authors

Nadezhda N. Nemstsveridze

Russian Research Institute of Hematology and Transfusiology

Author for correspondence.
Email: hope1704@mail.ru
ORCID iD: 0000-0002-3114-5902
SPIN-code: 2518-8667

hematologist, PhD student of FSBI RRIHT FMBA

Russian Federation, Saint Petersburg

Ekaterina V. Motyko

Russian Research Institute of Hematology and Transfusiology

Email: motyko@niigt.ru
ORCID iD: 0000-0002-6052-6472
SPIN-code: 4722-7754

Cand. Sci. (Biology), Head, Research Laboratory of Molecular Pathology

Russian Federation, Saint Petersburg

Anna N. Kirienko

Russian Research Institute of Hematology and Transfusiology

Email: kirienko@niigt.ru
ORCID iD: 0000-0002-2519-306X
SPIN-code: 5526-8437

Cand. Sci. (Biology), research associate

Russian Federation, Saint Petersburg

Daria V. Kustova

Russian Research Institute of Hematology and Transfusiology

Email: dasha_94-07@mail.ru
ORCID iD: 0000-0003-4546-5808
SPIN-code: 4778-4058

junior research associate

Russian Federation, Saint Petersburg

Irina S. Martynkevich

Russian Research Institute of Hematology and Transfusiology

Email: martynkevich@niigt.ru
ORCID iD: 0000-0001-5958-0490
SPIN-code: 2207-0439

Dr. Sci. (Biology), Head, Research Center for Cellular and Molecular Pathology

Russian Federation, Saint Petersburg

References

  1. Kumar A, Eyre TA, Lewis KL, et al. New Directions for Mantle Cell Lymphoma in 2022. American Society of Clinical Oncology Educational Book. 2022;42:614–628. doi: 10.1200/edbk_349509 EDN: QQAAPI
  2. Li S, Xu J, James You M. The pathologic diagnosis of mantle cell lymphoma. Histol Histopathol. 2021;36:1037–1051. doi: 10.14670/HH-18-351 EDN: BGOOHX
  3. Esmeray Sönmez E, Hatipoğlu T, Kurşun D, et al. Whole Transcriptome Sequencing Reveals Cancer-Related, Prognostically Significant Transcripts and Tumor-Infiltrating Immunocytes in Mantle Cell Lymphoma. Cells. 2022;11(21):3394. doi: 10.3390/cells11213394 EDN: KJRGIH
  4. Nadeu F, Martin-Garcia D, Clot G, et al. Genomic and epigenomic insights into the origin, pathogenesis, and clinical behavior of mantle cell lymphoma subtypes. Blood. 2020;136(12):1419–1432. doi: 10.1182/blood.2020005289 EDN: KIPWRF
  5. Gordon LI, Schieber M, Karmali R. Current overview and treatment of mantle cell lymphoma. F1000Research. 2018;7:1136. doi: 10.12688/f1000research.14122.1 EDN: WVTRAD
  6. Peterson JF, Baughn LB, Ketterling RP, et al. Characterization of a cryptic IGH/CCND1 rearrangement in a case of mantle cell lymphoma with negative CCND1 FISH studies. Blood Advances. 2019;3:1298–1302. doi: 10.1182/bloodadvances.2019031450
  7. Mishra P, Padhi S, Ayyanar P, et al. Clinicopathological and Immunohistochemical Profile of Mantle Cell Lymphoma: An Institutional Experience. Cureus. 2021;13(7):16534. doi: 10.7759/cureus EDN: AHTYPM
  8. Palomero J, Vegliante MC, Eguileor A, et al. SOX11 defines two different subtypes of mantle cell lymphoma through transcriptional regulation of BCL6. Leukemia. 2016;30:1580–1599. doi: 10.1038/leu.2015.355
  9. Silkenstedt E, Dreyling M, Bè S. Biological and clinical determinants shaping heterogeneity in mantle cell lymphoma. Blood Advances. 2024;8:3652–3664. doi: 10.1182/blood
  10. Navarro A, Beà S, Jares P, Campo E. Molecular Pathogenesis of Mantle Cell Lymphoma. Hematology. Oncology Clinics of North America. 2020;34:795–807. doi: 10.1016/j.hoc.2020.05.002 EDN: WQMYNG
  11. Navarro A, Royo C, Hernández L, et al. Molecular Pathogenesis of Mantle Cell Lymphoma: New Perspectives and Challenges With Clinical Implications. Seminars in Hematology. 2011;48:155–165. doi: 10.1053/j.seminhematol.2011.04.001
  12. Kleina EV, Voloshin SV, Semenova NYu, et al. Results of the study of cytogenetic and molecular genetic conditions in patients with mantle cell lymphoma. Hematology Transfusiology Eastern Europe. 2023;9(3):239–266. doi: 10.34883/pi.2023.9.3.004 EDN: VVURSZ
  13. Hill HA, Qi X, Jain P, et al. Genetic mutations and features of mantle cell lymphoma: A systematic review and meta-analysis. Blood Advances. 2020;4(13):2927–2938. doi: 10.1182/bloodadvances.2019001350 EDN: HWRFOL
  14. Li MM, Datto M, Duncavage EJ, et al. Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. Journal of Molecular Diagnostics. 2017;19(1):4–23. doi: 10.1016/j.jmoldx.2016.10.002
  15. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in Medicine. 2015;17(5):405–424. doi: 10.1038/gim.2015.30 EDN: UTYXCB
  16. Mayakonda A, Lin DC, Assenov Y, et al. Maftools: Efficient and comprehensive analysis of somatic variants in cancer. Genome Research. 2018;28(11):1747–1756. doi: 10.1101/gr.239244.118 EDN: JPTHUQ
  17. Halldórsdóttir AM, Lundin A, Murray F, et al. Impact of TP53 mutation and 17p deletion in mantle cell lymphoma. Leukemia. 2011;25(12):1904–1908. doi: 10.1038/leu.2011.162
  18. Wang L, Tang G, Medeiros LJ, et al. MYC rearrangement but not extra MYC copies is an independent prognostic factor in patients with mantle cell lymphoma. Haematologica. 2021;106:1381–1389. doi: 10.3324/haematol.2019.243071 EDN: HBCGSV
  19. Inamdar AA, Goy A, Ayoub NM, et al. Mantle cell lymphoma in the era of precision medicine-diagnosis, biomarkers and therapeutic agents. Oncotarget. 2016;7:48692–48731. doi: 10.18632/oncotarget.8961 EDN: WSOXIT
  20. Koff JL, Kositsky R, Jaye DL, et al. Mutations of ATM Confer a Risk of Inferior Survival in Patients with TP53- wild Type Mantle Cell Lymphoma. Blood. 2022;140(1):3500–3503. doi: 10.1182/blood-2022-168002
  21. Hoang NM, Liu Y, Bates PD, et al. Targeting DNMT3A-mediated oxidative phosphorylation to overcome ibrutinib resistance in mantle cell lymphoma. Cell Reports Medicine. 2024;5(4):101484. doi: 10.1016/j.xcrm.2024.101484 EDN: ZXNIKU
  22. Beà S, Valdés-Mas R, Navarro A, et al. Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. Proceeding of The National Academy of Science of The USA. 2013;110:18250–18255. doi: 10.1073/pnas.1314608110
  23. Ferrero S, Rossi D, Rinaldi A, et al. KMT2D mutations and TP53 disruptions are poor prognostic biomarkers in mantle cell lymphoma receiving high-dose therapy: A FIL study. Haematologica. 2020;105:1604–1612. doi: 10.3324/haematol.2018.214056
  24. Jain P, Wang ML. Mantle cell lymphoma in 2022-A comprehensive update on molecular pathogenesis, risk stratification, clinical approach, and current and novel treatments. American Journal of Hematology. 2022;97:638–656. doi: 10.1002/ajh.26523 EDN: NTLVCV
  25. Inamdar AA, Loo A, Mikhail N, et al. An aggressive presentation of Mantle Cell Lymphoma with unique molecular features. Cureus. 2021;13(8):e17598. doi: 10.7759/cureus.17598 EDN: ZZXAHS
  26. Messina M, Giudice I Del, Khiabanian H, et al. Genetic lesions associated with chronic lymphocytic leukemia chemo-refractoriness. Blood. 2014;123(15):2378–2388. doi: 10.1182/blood-2013-10-534271 EDN: SPUAFB
  27. Khouja M, Jiang L, Pal K, et al. Comprehensive genetic analysis by targeted sequencing identifies risk factors and predicts patient outcome in Mantle Cell Lymphoma: results from the EU-MCL network trials. Leukemia. 2024;38:2675–2684. doi: 10.1038/s41375-024-02375-8 EDN: MLZWIN
  28. Agarwal R, Chan YC, Tam CS, et al. Dynamic molecular monitoring reveals that SWI-SNF mutations mediate resistance to ibrutinib plus venetoclax in Mantle Cell Lymphoma. Nature. 2019;25:119–129. doi: 10.1038/s41591-018-0243-z EDN: ZUQYTH

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