INVESTIGATION OF CYTOGENETIC ABNORMALITIES IN NEWLY DIAGNOSED MULTIPLE MYELOMA PATIENTS BY OPTICAL GENOME MAPPING

Öz

Objective: Multiple myeloma (MM) is a neoplasm characterised by malignant proliferation of plasma cells. The FISH study on plasma cells is the main tool for cytogenetic analysis. Optical genome mapping (OGM) uses a combination of cytogenetic, FISH, and chromosomal microarray techniques to detect abnormalities with greater sensitivity. In this study, we aimed to illuminate the lesser-known cytogenetic aspects of MM using OGM.

Materials and Methods: This study was conducted on five patients diagnosed with MM. Bone marrow samples were collected and used for flow cytometry to isolate plasma cells. OGM could not be performed in two patients. FISH was conducted on bone marrow, whereas OGM was performed on plasma cells.

Results: Patient 1 had a ploidy abnormality, as revealed by FISH. Patient 2 had monosomy 13 detected by FISH; in addition, OGM revealed 10 aneuploidies, two deletions, and one duplication. No abnormalities were detected in the regions analysed by FISH in Patient 3. Along with trisomy 1q21 detected by FISH, Patient 4 had 11 copy number variations (CNVs), 10 structural variants (SVs), and seven aneuploidies detected by OGM. In Patient 5, FISH revealed trisomy 1q21, monosomy 13, and trisomy 17. OGM detected 12 aneuploidies and two CNVs.

Conclusion: In MM, the use of OGM, which provides more detailed karyotypic classification, may provide valuable prognostic information for clinical practice. Newly identified abnormalities with OGM may contribute to our understanding of the aetiology and pathogenesis of the disease.

Anahtar Kelimeler

• Multiple myeloma
• Fluorescence in situ hybridization
• Genomic structural variation
• genome mapping

YENİ TANILI MULTİPL MİYELOM HASTALARINDA SİTOGENETİK ANOMALİLERİN OPTİK GENOM HARİTALAMA İLE ARAŞTIRILMASI

Öz

Amaç: Multipl miyeloma (MM), malign plazma hücrelerinin proliferasyonu ile karakterize bir neoplazidir. Plazma hücreleri üzerinde yapılan floresan in situ hibridizasyon (FISH) incelemesi, sitogenetik analiz için ana araçtır. Optik genom haritalama (OGM), anomalileri daha yüksek hassasiyetle tespit etmek için sitogenetik, FISH ve kromozomal mikroarray tekniklerinin bir kombinasyonunu kullanır. Bu çalışmada, OGM’nın kullanılması ile MM’nin daha az bilinen sitogenetik yönlerinin aydınlatılması amaçlandı.

Gereç ve Yöntemler: Bu çalışma, MM tanısı konulan beş olguda gerçekleştirildi. Kemik iliği örnekleri alındı ve akış sitometrisi ile plazma hücreleri izole edildi. İki olguda OGM yapılamadı. Tüm olgularda, FISH incelemesi kemik iliği, OGM ise plazma hücreleri kullanılarak yapıldı.

Bulgular: Olgu 1’de FISH ile ploidiyi düşündüren bir anomali saptandı. Olgu 2’de FISH ile monozomi 13 saptandı; ayrıca OGM ile 10 anöploidi, iki delesyon ve bir duplikasyon saptandı. Olgu 3’te FISH ile analiz edilen bölgelerde anomali tespit edilmedi. Olgu 4’te FISH ile tespit edilen 1q21 trizomisine ek olarak OGM ile 11 kopya sayısı varyasyonu (CNV), 10 yapısal varyant (SV) ve yedi anöploidi saptandı. Olgu 5’te FISH; 1q21 trizomisi, kromozom 13 monozomisi ve kromozom 17 trizomisini ortaya çıkardı. OGM 12 anöploidi ve iki CNV tespit etti.

Sonuç: MM’de daha ayrıntılı karyotipik sınıflandırma sağlayan OGM kullanımı, klinik uygulama için değerli prognostik bilgiler sağlayabilir. OGM ile yeni tanımlanan anomaliler, hastalığın etiyolojisi ve patogenezini anlamamıza katkıda bulunabilir.

Anahtar Kelimeler

• Multipl miyeloma
• Floresan in situ hibridizasyon
• Genomik yapısal varyasyon
• optik genom haritalama

Kaynakça

1. Castaneda O, Baz R. Multiple Myeloma Genomics - A Concise Review. Acta Med Acad 2019;48(1):57-67. google scholar
2. Cowan AJ, Green DJ, Kwok M, Lee S, Coffey DG, Holmberg LA, et al. Diagnosis and Management of Multiple Myeloma: A Review. JAMA 2022;327(5):464-77. google scholar
3. Clarke SE, Fuller KA, Erber WN. Chromosomal defects in multiple myeloma. Blood Rev 2024;64:101168. google scholar
4. Coccaro N, Anelli L, Zagaria A, Tarantini F, Cumbo C, Tota G, et al. Feasibility of Optical Genome Mapping in Cytogenetic Diagnostics of Hematological Neoplasms: A New Way to Look at DNA. Diagnostics (Basel) 2023;13(11):1841. google scholar
5. Erdem, S, Bayrak Tokaç AG, Aday A, Karaca D, Mutlu MB, Çefle K, et al. Pilot evaluation of optical genome mapping in chronic lymphocytic leukemia: complementing FISH analysis. BMC Cancer 2025;25:1687. google scholar
6. Wang X, Rong S, Sun Y, Yin B, Yang X, Lu X, et al. NDRG3 regulates imatinib resistance by promoting β‑catenin accumulation in the nucleus in chronic myelogenous leukemia. Oncol Rep. 2023;50(2):152. google scholar
7. Athanasopoulou K, Adamopoulos PG, Daneva GN, Scorilas A. Decoding the concealed transcriptional signature of the apoptosis-related BCL2 antagonist/killer 1 (BAK1) gene in human malignancies. Apoptosis 2022;27(11-12):869-82. google scholar
8. Elzamzamy OM, Johnson BE, Chen WC, Hu G, Penner R, Hazlehurst LA. Transient Receptor Potential C 1/4/5 Is a Determinant of MTI-101 Induced Calcium Influx and Cell Death in Multiple Myeloma. Cells 2021;10(6):1490. google scholar

9. Zhang Y, Zeng C, Lu S, Qin T, Yang L, Chen S, et al. Identification of miR-125b targets involved in acute promyelocytic leukemia cell proliferation. Biochem Biophys Res Commun 2016;478(4):1758-63. google scholar
10. Zhu Y, He J, Wei R, Liu J. Construction and experimental validation of a novel ferroptosis-related gene signature for myelodysplastic syndromes. Immun Inflamm Dis 2024;12(4):e1221. google scholar
11. Kometani K, Aoki M, Kawamata S, Shinozuka Y, Era T, Taniwaki M, et al. Role of SPA-1 in phenotypes of chronic myelogenous leukemia induced by BCR-ABL-expressing hematopoietic progenitors in a mouse model. Cancer Res 2006;66(20):9967-76. google scholar
12. Rabe JL, Gardner L, Hunter R, Fonseca JA, Dougan J, Gearheart CM, et al. IL12 Abrogates Calcineurin-Dependent Immune Evasion during Leukemia Progression. Cancer Res 2019;79(14):3702-13. google scholar
13. Robles-Rebollo I, Cuartero S, Canellas-Socias A, Wells S, Karimi MM, Mereu E, et al. Cohesin couples transcriptional bursting probabilities of inducible enhancers and promoters. Nat Commun 2022;13(1):4342. google scholar
14. Lu XX, Yang WX, Pei YC, Luo H, Li XG, Wang YJ, et al. An In Vivo CRISPR Screen Identifies That SNRPC Promotes Triple-Negative Breast Cancer Progression. Cancer Res 2023;83(12):2000-15. google scholar
15. Zhang Z, Zhang L, Li J, Feng R, Li C, Liu Y, et al. Comprehensive analysis of m⁶A methylome alterations after azacytidine plus venetoclax treatment for acute myeloid leukemia by nanopore sequencing. Comput Struct Biotechnol J 2024;23:1144-53. google scholar
16. Liu J, Xu J, Sun R, Wang X, Chen F, Fu Y, et al. MARCH1, transcriptionally regulated by POU2F2, facilitates acute myeloid leukemia progression via inducing MYCT1 degradation. Oncogene 2025;44(33):2983-96. google scholar
17. Almaghrbi H, Elkardawy R, Udhaya Kumar S, Kuttikrishnan S, Abunada T, Kashyap MK, et al. Analysis of signaling cascades from myeloma cells treated with pristimerin. Adv Protein Chem Struct Biol 2023;134:147-74. google scholar
18. Kubo N, Wu D, Yoshihara Y, Sang M, Nakagawara A, Ozaki T. Co-chaperon DnaJC7/TPR2 enhances p53 stability and activity through blocking the complex formation between p53 and MDM2. Biochem Biophys Res Commun 2013;430(3):1034-39. google scholar
19. Cottini F, Hideshima T, Xu C, Sattler M, Dori M, Agnelli L, et al. Rescue of Hippo coactivator YAP1 triggers DNA damage-induced apoptosis in hematological cancers. Nat Med 2014;20(6):599-606. google scholar
20. Zheng B, Sun W, Yi K, Zhang Y, Wang L, Lan H, et al. Integrated Transcriptomic Analysis Reveals a Distinctive Role of YAP1 in Extramedullary Invasion and Therapeutic Sensitivity of Multiple Myeloma. Front Oncol 2022;11:787814. google scholar
21. Zhang J, Zhang R. Megalosplenia as an initial manifestation of multiple myeloma with a novel CYLD gene mutation: A case report and literature review. Medicine (Baltimore) 2024;103(14):e37624. google scholar
22. Mateos MV, San Miguel JF. Management of multiple myeloma in the newly diagnosed patient. Hematology Am Soc Hematol Educ Program 2017;2017(1):498-507. google scholar
23. Takada S, Morita K, Hayashi K, Matsushima T, Sawamura M, Murakami H, et al. Methylation status of fragile histidine triad (FHIT) gene and its clinical impact on prognosis of patients with multiple myeloma. Eur J Haematol 2005;75(6):505-10. google scholar
24. Avet-Loiseau H, Davies FE, Samur MK, Corre J, D'Agostino M, Kaiser MF, et al. Erratum: International Myeloma Society/International Myeloma Working Group Consensus Recommendations on the Definition of High-Risk Multiple Myeloma. J Clin Oncol 2025;43(22):2553. google scholar
25. Dimopoulos MA, Terpos E, Boccadoro M, Moreau P, Mateos MV, Zweegman S, et al. EHA-EMN Evidence-Based Guidelines for diagnosis, treatment and follow-up of patients with multiple myeloma. Nat Rev Clin Oncol 2025;22(9):680-700. google scholar
26. Giguère A, Raymond-Bouchard I, Collin V, Claveau JS, Hébert J, LeBlanc R. Optical Genome Mapping Reveals the Complex Genetic Landscape of Myeloma. Cancers (Basel) 2023;15(19):4687. google scholar
27. Bayrak Tokaç AG, Mutlu MB, Erdem S, Aday A. Optical Genome Mapping as a New Approach to Detecting Cytogenetic Abnormalities: Why Is It Difficult in Multiple Myeloma?. Turk J Haematol 2025;42(2):165-66. google scholar
28. Kriegova E, Fillerova R, Minarik J, Savara J, Manakova J, Petrackova A, et al. Whole-genome optical mapping of bone-marrow myeloma cells reveals association of extramedullary multiple myeloma with chromosome 1 abnormalities. Sci Rep 2021;11(1):14671. google scholar
29. Zou YS, Klausner M, Ghabrial J, Stinnett V, Long P, Morsberger L, et al. A comprehensive approach to evaluate genetic abnormalities in multiple myeloma using optical genome mapping. Blood Cancer J 2024;14(1):78. google scholar
30. Levy B, Baughn LB, Akkari Y, Chartrand S, LaBarge B, Claxton D, et al. Optical genome mapping in acute myeloid leukemia: a multicenter evaluation. Blood Adv 2023;7(7):1297-1307. google scholar
31. Palacios, JA, Bernal M, Vílchez JR, Garrido P, Jiménez P, Gutiérrez-Bautista J F, et al. Optical genome mapping reveals complex cytogenetic abnormalities in multiple myeloma. Haematologica 2025;110(12):3133-39. google scholar
32. Cisneros A, Mallo M, Méndez-López A, Villena C, Santafé E, Tijero J, et al. Optical Genome Mapping (OGM): Validation and Clinical Utility in the Cytogenetic Diagnosis of Multiple Myeloma. Am J Hematol 2025;100(11):2114-17. google scholar
33. Yoon J, Kwon JA, Yoon SY. Clinical Validation of Optical Genome Mapping in Multiple Myeloma Without Plasma Cell Enrichment. Am J Hematol 2025;100(4):700-3. google scholar
34. Wiedmeier-Nutor JE, Fonseca R. Hyperdiploid myeloma: The silent majority. Br J Haematol 2025;207(2):365-68. google scholar
35. Kadam Amare P, Nikalje Khasnis S, Hande P, Lele H, Wable N, Kaskar S, et al. Cytogenetic Abnormalities in Multiple Myeloma: Incidence, Prognostic Significance, and Geographic Heterogeneity in Indian and Western Populations. Cytogenet Genome Res 2022;162(10):529-40. google scholar
36. Gerding WM, Tembrink M, Nilius-Eliliwi V, Mika T, Dimopoulos F, Ladigan-Badura S, et al. Optical genome mapping reveals additional prognostic information compared to conventional cytogenetics in AML/MDS patients. Int J Cancer 2022;150(12):1998-2011. google scholar
37. Gao H, Xu H, Wang C, Cui L, Huang X, Li W, et al. Optical Genome Mapping for Comprehensive Assessment of Chromosomal Aberrations and Discovery of New Fusion Genes in Pediatric B-Acute Lymphoblastic Leukemia. Cancers (Basel) 2022;15(1):35. google scholar
38. Guermouche H, Roynard P, Servoli F, Lestringant V, Quilichini B, Terré C, et al. Deciphering Genomic Complexity of Multiple Myeloma Using Optimized Optical Genome Mapping. J Mol Diagn 2025;27(4):306-22. google scholar
39. Toruner GA, Hu S, Loghavi S, Ok CY, Tang Z, Wei Q, et al. Clinical Utility of Optical Genome Mapping as an Additional Tool in a Standard Cytogenetic Workup in Hematological Malignancies. Cancers (Basel) 2025;17(9):1436. google scholar
40. Levy B, Burnside RD, Akkari Y. Optical Genome Mapping: A New Tool for Cytogenomic Analysis. Genes (Basel) 2025;16(8):924. google scholar
41. Dremsek P, Schwarz T, Weil B, Malashka A, Laccone F, Neesen J. Optical Genome Mapping in Routine Human Genetic Diagnostics-Its Advantages and Limitations. Genes (Basel) 2021;12(12):1958. google scholar