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Multiple Myeloma Hastalarında Sitokin Gen Polimorfizmleri ve Kromozom 13 Delesyonu

Year 2020, Volume: 3 Issue: 3, 179 - 185, 05.11.2020

Abstract

Amaç: Multiple myeloma (MM), plazma hücrelerinin kemik iliği, lenfoid dokular ve çevre kanında birikmesidir. MM’de görülen en sık anomalilerden biri 13/13q delesyonudur ve yaklaşık %40-50 oranında görülür. Yapılan çalışmalar, hastaların çoğunda kromozom anomalisinin %80-90’ının monozomi 13 şeklinde iken %10-20’sinin bölgesel delesyonlar şeklinde olduğunu göstermiştir. Monozomi 13, sağkalımı belirleyen en önemli belirteçlerden biridir. Sitokinler, immün sistem hücrelerince salınan ve bu hücrelerin birçok fonksiyonunu düzenleyen proteinlerdir. Plazma hücresi, immünglobin üretiminde IL-1β, IL-6, IL-10 ve TNF-α gibi sitokinleri üretirler. Tek nükleotid polimorfizmleri de tek amino asit değişikliği ile sitokin fonksiyonunda ve üretiminde farklılıklar oluştururlar. Sitokinler ve kromozom 13 delesyonu (del13), MM hastalığı için önemli olan faktörlerden ikisidir. Biz de çalışmamızda MM ile del13 ve 10 sitokin (IL-1α, IL-1β, IL- 12, IFN-γ, TGF-β, TNF-α, IL-2, IL-4, IL-6, IL-10), 2 reseptör (IL-1R, IL-4Rα) ve 1 reseptör antagonistinin (IL-1RA) gen polimorfizmleri arasındaki ilişkiyi incelemeyi amaçladık. Gereç ve Yöntem: Çalışmaya multiple myeloma tanısı konmuş 38 hasta dahil edildi. Sitokin gen polimorfizm tiplemesi için PCR-SSP yöntemi kullanıldı (Protrans). Delesyon 13 için LSI D13S25 SO DNA probu kullanılarak FISH yöntemi uygulandı. Bulgular: Hastaların %40’ında del 13 saptandı. 13q delesyonu ve sitokin gen polimorfizmlerinin ayrı ayrı hasta yaşı, cinsiyeti, hastalık evresi ve β2-mikroglobulin seviyeleri ile istatistiksel analizi sonucu anlamlı bir değer gözlenmedi. LDH düzeyi ile TGF-β TG/TG haplotipi arasında istatistiksel anlamlılık saptandı (p:0.002). Sitokin polimorfizmleri ve del13 arasındaki ilişkiye bakıldığında anlamlı bir sonuç elde edilmedi (p>0.05). Sonuç: Sitokin polimorfizmi ve del13 varlığının hastalığın prognozu üzerine ayrı ayrı etkisi olsa da iki parametrenin birlikte prognoz üzerine etkisi saptanamadı.

References

  • 1. Caligaris CF, Gregoretti MG, Merico F, Gottardi D, Ghia P, Parvis G, et al. Bone marrow microenvironment and the progression of multiple myeloma. Leuk Lymphoma 1992;8(1- 2):15-22.
  • 2. Angtuago EJ, Fassas AB, Walker R, Sethi R, Barlogie B. Multiple myeloma: clinical review and diagnostic imaging. Radiology 2004;231(1):11- 23.
  • 3. Stellrecht CM, Gandhi V. Myeloma antioxidant status: the good, the bad and reactive. Leuk Lymphoma 2009;50(5):691-3.
  • 4. Banu C, Moise A, Arion CR, Coriu D, Tanase A, Constantinescu I. Cytokine gene polymorphisms support diagnostic monitoring of Romanian multiple myeloma patients. J Med Life 2011;4(3):264-8.
  • 5. Vangsted AJ, Klausen TW, Ruminski W, Gimsing P, Andersen NF, Gang AO, et al. The polymorphism IL-1 beta T-31C is associated with a longer overall survival in patients with multiple myeloma undergoing auto-SCT. Bone Marrow Transp 2009;43(7):539-45.
  • 6. Wang H, Gao C, Xu L, Yang Z, Zhao W, Kong X. Laboratory characterizations on 2007 cases of monoclonal gammopathies in east china. Cell Mol Immunol 2008;5(4):293-8.
  • 7. Leigh JK. The extent and analysis of cytokine and cytokine receptor gene polymorphism. Transplan Immunol 2002;10:143-6.
  • 8. Ollier WE. Cytokine genes and disease susceptibility. Cytokine 2004;28(4-5):174-8.
  • 9. Ho PJ. Chromosomal and genetic abnormalities in myeloma. Clin Lab Haem 2002;24(5):259-69
  • 10. Liebisch P, Wendl C, Wellmann A, Kröber A, Schilling G, Goldschmidt H, et al. High incidence of trisomies 1q, 9q, and 11q in multiple myeloma: results from a comprehensive molecular cytogenetic analysis. Leukemia 2003;17:2535-7.
  • 11. Perez-Simon JA, Garcia-Sanz R, Tabernero MD, Bladé J, Moro MJ, Fernández-Calvo J, et al. Prognostic value of numerical chromosome aberrations in multiple myeloma: A FISH analysis of 15 different chromosomes. Blood 1998;91(9):3366–71.
  • 12. Zojer N, Königsberg R, Ackermann J, Fritz E, Dallinger S, Krömer E, et al. Deletion of 13q14 remains an independent adverse prognostic variable in multiple myeloma despite its frequent detection by interphase fluorescence in situ hybridization. Blood 2000;95(6):1925–30.
  • 13. Facon T, Avet-Loiseau H, Guillerm G, Moreau P, Geneviève F, Zandecki M, et al. Chromosome 13 abnormalities identified by FISH analysis and serum ß-2-microglobulin produce a powerful myeloma staging system for patients receiving high-dose therapy. Blood 2001;97(6):1566–71.
  • 14. Fonseca R, Harrington D, Oken M, Dewald GW, Bailey RJ, Van Wier SA, et al. Biologic and prognostic significance of interphase FISH detection of chromosome 13 abnormalities (D13) in multiple myeloma: an Eastern Cooperative Oncology Group (ECOG) Study. Cancer Res 2002;62(3):715–20.
  • 15. Gustincich S, Manfiolett G, Del Sal G, Schneider C, Carninci P. A fast method for high-quality genomic DNA extraction from whole human blood. Bio Techniques 1991;11(3):298-302.
  • 16. Olerup O, Zetterquist H. DR low resolution PCR-SSP typing –a correction and an up-date. Tissue Antigens 1993;41(1):55-6.
  • 17. Özdilli K, Aydın F, Beşışık SK, Oğuz F, Temurhan S, Çako Ö, et al. Detection of chromosomal abnormalities on interface cells from myeloid leukemias by FISH. Nobel Med 2010; 6(3): 84-89.
  • 18. Fonseca R, Oken MM, Harrington D, Bailey RJ, Van Wier SA, Henderson KJ, et al. Deletions of chromosome 13 in multiple myeloma identified by interphase FISH usually denote large deletions of the q arm or monosomy. Leukemiz 2001;15(6):981-6.
  • 19. Chakraborty B, Vishnoi G, Gowda SH, Goswami B. Interleukin-6 gene-174 G/C promoter polymorphism and its association with clinical profile of patients with multiple myeloma. Asia- Pac J Clin Oncol 2014;13(5):e402-e407.
  • 20. G Mazur, K Bogunia-Kubik, T Wróbel, L Karabon, M Polak, K Kuliczkowski, et al. IL-6 and IL-10 promoter gene polymorphisms do not associate with the susceptibility for multiple myeloma. Immunol Lett 2005;96(2):241-6.
  • 21. Iakupova EV, Grinchuk OV, Kalimullina D, Bakirov B, Galimova RR, Makarova OV, et al. Molecular genetic analysis of the Interleukin 6 and Tumor Necrosis Factor a gene polymorphisms in multiple myeloma. Mol Biol (Mosk) 2003;37:420-4.

Cytokine Gene Polymorphisms and Chromosome 13 Deletion in Multiple Myeloma Patients

Year 2020, Volume: 3 Issue: 3, 179 - 185, 05.11.2020

Abstract

Objective: Multiple myeloma (MM) is a clonal enlargement of plasma cells. The most common cytogenetic anomaly in MM is monosomy 13 and appears approximately 40%–50% in multiple myeloma. Studies have shown that in the majority of patients, 80%–90% of chromosomal anomalies are monosomy 13, and 10%–20% are regional deletions. Monosomy 13 is the most powerful predictor of survival in MM. Cytokines are proteins that regulate many functions of these cells and are secreted by cells of the immune system. Plasma cell stimulates angiogenesis by increasing the release of cytokines such as IL-1β, IL-6, and IL-10. Single nucleotide polymorphisms (SNP) of cytokine genes can affect their secretion rate or biological activity. Two of the important factors for MM disease are cytokines and chromosome 13 deletion (del13). We investigate chromosome 13 deletion and cytokine gene polymorphisms (IFN-γ, TGF-β, TNF-α, IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL-1R, IL-1Rα, IL-4Rα) in patients with MM. Materials and Methods: EDTA blood was collected from 38 patients with MM included in the study, and DNA was isolated. PCR-SSP method was used for cytokine gene polymorphism typing (Protrans). FISH method was applied using LSI D13S25 SO DNA probe for deletion 13. Results: 13q deletion was detected in 15 of the 38 of the patients. Statistical analysis of 13q deletion and cytokine gene polymorphisms was not statistically significant (p>0.05) by patient age, sex, disease stage, and β2-microglobulin levels. There is a statistical significance between level of LDH and TGF-β TG/TG haplotype (p=0.002). No significant results were obtained in the relationship between cytokine polymorphisms and del13 (p>0.05). Conclusion: Cytokines, which are associated with the function and viability of plasma cells, have a major role in the etiology and prognosis of the disease. Moreover, similar effects were observed with the 13q deletion. In our study, we did not find a statistical significance between cytokine gene polymorphisms and 13q deletion. Although both parameters independently have great importance on the effects of the disease, combining them together does not yield the same effect.

References

  • 1. Caligaris CF, Gregoretti MG, Merico F, Gottardi D, Ghia P, Parvis G, et al. Bone marrow microenvironment and the progression of multiple myeloma. Leuk Lymphoma 1992;8(1- 2):15-22.
  • 2. Angtuago EJ, Fassas AB, Walker R, Sethi R, Barlogie B. Multiple myeloma: clinical review and diagnostic imaging. Radiology 2004;231(1):11- 23.
  • 3. Stellrecht CM, Gandhi V. Myeloma antioxidant status: the good, the bad and reactive. Leuk Lymphoma 2009;50(5):691-3.
  • 4. Banu C, Moise A, Arion CR, Coriu D, Tanase A, Constantinescu I. Cytokine gene polymorphisms support diagnostic monitoring of Romanian multiple myeloma patients. J Med Life 2011;4(3):264-8.
  • 5. Vangsted AJ, Klausen TW, Ruminski W, Gimsing P, Andersen NF, Gang AO, et al. The polymorphism IL-1 beta T-31C is associated with a longer overall survival in patients with multiple myeloma undergoing auto-SCT. Bone Marrow Transp 2009;43(7):539-45.
  • 6. Wang H, Gao C, Xu L, Yang Z, Zhao W, Kong X. Laboratory characterizations on 2007 cases of monoclonal gammopathies in east china. Cell Mol Immunol 2008;5(4):293-8.
  • 7. Leigh JK. The extent and analysis of cytokine and cytokine receptor gene polymorphism. Transplan Immunol 2002;10:143-6.
  • 8. Ollier WE. Cytokine genes and disease susceptibility. Cytokine 2004;28(4-5):174-8.
  • 9. Ho PJ. Chromosomal and genetic abnormalities in myeloma. Clin Lab Haem 2002;24(5):259-69
  • 10. Liebisch P, Wendl C, Wellmann A, Kröber A, Schilling G, Goldschmidt H, et al. High incidence of trisomies 1q, 9q, and 11q in multiple myeloma: results from a comprehensive molecular cytogenetic analysis. Leukemia 2003;17:2535-7.
  • 11. Perez-Simon JA, Garcia-Sanz R, Tabernero MD, Bladé J, Moro MJ, Fernández-Calvo J, et al. Prognostic value of numerical chromosome aberrations in multiple myeloma: A FISH analysis of 15 different chromosomes. Blood 1998;91(9):3366–71.
  • 12. Zojer N, Königsberg R, Ackermann J, Fritz E, Dallinger S, Krömer E, et al. Deletion of 13q14 remains an independent adverse prognostic variable in multiple myeloma despite its frequent detection by interphase fluorescence in situ hybridization. Blood 2000;95(6):1925–30.
  • 13. Facon T, Avet-Loiseau H, Guillerm G, Moreau P, Geneviève F, Zandecki M, et al. Chromosome 13 abnormalities identified by FISH analysis and serum ß-2-microglobulin produce a powerful myeloma staging system for patients receiving high-dose therapy. Blood 2001;97(6):1566–71.
  • 14. Fonseca R, Harrington D, Oken M, Dewald GW, Bailey RJ, Van Wier SA, et al. Biologic and prognostic significance of interphase FISH detection of chromosome 13 abnormalities (D13) in multiple myeloma: an Eastern Cooperative Oncology Group (ECOG) Study. Cancer Res 2002;62(3):715–20.
  • 15. Gustincich S, Manfiolett G, Del Sal G, Schneider C, Carninci P. A fast method for high-quality genomic DNA extraction from whole human blood. Bio Techniques 1991;11(3):298-302.
  • 16. Olerup O, Zetterquist H. DR low resolution PCR-SSP typing –a correction and an up-date. Tissue Antigens 1993;41(1):55-6.
  • 17. Özdilli K, Aydın F, Beşışık SK, Oğuz F, Temurhan S, Çako Ö, et al. Detection of chromosomal abnormalities on interface cells from myeloid leukemias by FISH. Nobel Med 2010; 6(3): 84-89.
  • 18. Fonseca R, Oken MM, Harrington D, Bailey RJ, Van Wier SA, Henderson KJ, et al. Deletions of chromosome 13 in multiple myeloma identified by interphase FISH usually denote large deletions of the q arm or monosomy. Leukemiz 2001;15(6):981-6.
  • 19. Chakraborty B, Vishnoi G, Gowda SH, Goswami B. Interleukin-6 gene-174 G/C promoter polymorphism and its association with clinical profile of patients with multiple myeloma. Asia- Pac J Clin Oncol 2014;13(5):e402-e407.
  • 20. G Mazur, K Bogunia-Kubik, T Wróbel, L Karabon, M Polak, K Kuliczkowski, et al. IL-6 and IL-10 promoter gene polymorphisms do not associate with the susceptibility for multiple myeloma. Immunol Lett 2005;96(2):241-6.
  • 21. Iakupova EV, Grinchuk OV, Kalimullina D, Bakirov B, Galimova RR, Makarova OV, et al. Molecular genetic analysis of the Interleukin 6 and Tumor Necrosis Factor a gene polymorphisms in multiple myeloma. Mol Biol (Mosk) 2003;37:420-4.
There are 21 citations in total.

Details

Primary Language English
Subjects Clinical Sciences
Journal Section Research Article
Authors

Çiğdem Kekik 0000-0003-2098-381X

Gonca Karahan This is me 0000-0001-5339-7126

Sonay Temurhan 0000-0001-9889-9330

Sevgi Kalayoğlu Beşışık This is me 0000-0002-9310-1278

Fatma Savran Oğuz 0000-0002-6018-8936

Filiz Aydın 0000-0001-5984-7538

Publication Date November 5, 2020
Submission Date September 29, 2020
Published in Issue Year 2020 Volume: 3 Issue: 3

Cite

MLA Kekik, Çiğdem et al. “Cytokine Gene Polymorphisms and Chromosome 13 Deletion in Multiple Myeloma Patients”. Sağlık Bilimlerinde İleri Araştırmalar Dergisi, vol. 3, no. 3, 2020, pp. 179-85.