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The association of Hypoxia-Inducible Factor-2α (HIF-2α) overexpression score with Germinal Center B-Cell Like (GCB) and Non-Germinal Center B-Cell Like (Non-GCB) subtypes of Diffuse Large B-cell Lymphoma (DLBCL)

  • Eko Adhi Pangarsa ,
  • Desta Nur Ewika Ardini ,
  • Daniel Rizky ,
  • Kevin Tandarto ,
  • Hermawan Istiadi ,
  • Dik Puspasari ,
  • Budi Setiawan ,
  • Damai Santosa ,
  • Hertanto Wahyu Subagio ,
  • Tri Indah Winarni ,
  • Sofia Mubarika Haryana ,
  • Catharina Suharti ,


Abstract

Link of Video Abstract: https://www.youtube.com/watch?v=KF58IGGdWmc

 

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma. It is classified into homogeneous subtypes, namely Germinal Center B-Cell Like (GCB) and Non-Germinal Center B-Cell Like (GCB), with the latter associated with worse survival outcomes. Increased expression of Hypoxia-Inducible Factor-2α (HIF-2α) is often observed in DLBCL and has been correlated with enhanced angiogenesis, suggesting its potential as a prognostic factor in managing DLBCL. The study evaluates the association between HIF-2α overexpression and the GCB and non-GCB subtypes of DLBCL.

Methods: This cross-sectional study utilized samples from DLBCL patients at Dr. Kariadi Semarang Hospital between January and December 2021. Immunohistochemistry was performed on the samples to determine the DLBCL subtypes and assess the presence of HIF-2α. HIF-2α was evaluated by immunohistochemistry based on its distribution and intensity. The Kruskal-Wallis test was used to find the association between HIF-2α expression and the GCB and non-GCB subtypes of DLBCL. Furthermore, Spearman's rank correlation test explored the correlation between all numeric variables.

Results: A total of 30 subjects were included in this study, with 7 samples of GCB subtype (23.3%) and 23 samples of non-GCB subtype (76.6%). Kruskal-Wallis test showed no association between HIF-2α expression and the subtypes of DLBCL (p=0.812). Spearman's rho correlation test indicated no correlation between HIF-2α overexpression score with NCCN IPI score in GCB (r=0.219; p=0.637) and non-GCB (r=-0.194; p=0.386).

Conclusion: There was no association between HIF-2α expression and GCB and non-GCB subtypes of DLBCL. Additionally, no correlation was found between HIF-2α overexpression and NCCN IPI score.

Keywords: DLBCL HIF-2 GCB non-CB Lymphoma

References

  1. Qin W, Fu D, Shi Q, Dong L, Yi H, Huang H, et al. Molecular Heterogeneity in Localized Diffuse Large B-Cell Lymphoma. Front Oncol. 2021;11:638757.
  2. Liu Y, Barta SK. Diffuse large B-cell lymphoma: 2019 update on diagnosis, risk stratification, and treatment. Am J Hematol. 2019;94(5):604-616.
  3. Ruppert AS, Dixon JG, Salles G, Wall A, Cunningham D, Poeschel V, et al. International prognostic indices in diffuse large B-cell lymphoma: a comparison of IPI, R-IPI, and NCCN-IPI. Blood. 2020;135(23):2041-2048.
  4. Boltežar L, Prevodnik VK, Perme MP, Gašljević G, Novaković BJ. Comparison of the algorithms classifying the ABC and GCB subtypes in diffuse large B-cell lymphoma. Oncol Lett. 2018;15(5):6903-6912.
  5. Albadari N, Deng S, Li W. The transcriptional factors HIF-1 and HIF-2 and their novel inhibitors in cancer therapy. Expert Opin Drug Discov. 2019;14(7):667-682.
  6. Bosco MC, D'Orazi G, Del Bufalo D. Targeting hypoxia in tumor: a new promising therapeutic strategy. J Exp Clin Cancer Res. 2020;39(1):8.
  7. Muz B, de la Puente P, Azab F, Luderer M, Azab AK. The role of hypoxia and exploitation of the hypoxic environment in hematologic malignancies. Mol Cancer Res. 2014;12(10):1347-1354.
  8. Wigerup C, Påhlman S, Bexell D. Pharmacology & Therapeutics Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. Pharmacol Ther. 2016;164:152–169.
  9. Löfstedt T, Fredlund E, Holmquist-Mengelbier L, Pietras A, Ovenberger M, Poellinger L, et al. Hypoxia inducible factor-2alpha in cancer. Cell Cycle. 2007;6(8):919-926.
  10. Jarman EJ, Ward C, Turnbull AK, Martinez-Perez C, Meehan J, Xintaropoulou C, et al. HER2 regulates HIF-2α and drives an increased hypoxic response in breast cancer. Breast Cancer Res. 2019;21(1):10.
  11. Evens AM, Schumacker PT, Helenowski IB, Singh AT, Dokic D, Keswani A, et al. Hypoxia inducible factor-alpha activation in lymphoma and relationship to the thioredoxin family. Br J Haematol. 2008;141(5):676-680.
  12. Reksodiputro AH. Multicentre Epidemiology and Survival Study of B Cell Non-Hodgkin Lymphoma Patients In Indonesia. J Blood Disord Transfus. 2015;6(2):1–5.
  13. Huh J. Epidemiologic overview of malignant lymphoma. Korean J Hematol. 2012;47(2):92-104.
  14. Tarius JM, Istiadi H, Miranti IP, Dini IRE. The correlation between cell of origin subtype with overall survival of diffuse large B-cell lymphoma patients in Kariadi General Hospital Semarang. Diponegoro Med J. 2020;9(3):252–258.
  15. Wawire J, Sayed S, Moloo Z, Sohani AR. Diffuse Large B-Cell Lymphoma in Kenya: MYC, BCL2, and the Cell of Origin. J Glob Oncol. 2019;5:1-8.
  16. Alavanja MC, Hofmann JN, Lynch CF, Hines CJ, Barry KH, Barker J, et al. Non-hodgkin lymphoma risk and insecticide, fungicide and fumigant use in the agricultural health study. PLoS One. 2014;9(10):e109332.
  17. Bidang Integrasi DP. Jawa Tengah in Figures. Badan Pusat Statistik Provinsi Jawa Tengah. 2019.
  18. Hwang HS, Kim M, Park CS, Yoon DH, Suh C, Huh J, et al. Prognostic Impact of Age at the Time of Diagnosis in Korean Patients with Diffuse Large B-cell Lymphoma in the Rituximab Era: A Single Institution Study. Cancer Res Treat. 2021;53(1):270-278.
  19. Drozd-Sokolowska J, Zaucha JM, Biecek P, Giza A, Kobylinska K, Joks M, et al. Type 2 diabetes mellitus compromises the survival of diffuse large B-cell lymphoma patients treated with (R)-CHOP - the PLRG report. Sci Rep. 2020;10(1):3517.
  20. Tisi MC, Bozzoli V, Giachelia M, Massini G, Ricerca BM, Maiolo E, et al. Anemia in diffuse large B-cell non-Hodgkin lymphoma: the role of interleukin-6, hepcidin and erythropoietin. Leuk Lymphoma. 2014;55(2):270-275.
  21. Clausen MR, Maurer MJ, Ulrichsen SP, Larsen TS, Himmelstrup B, Rønnov-Jessen D, et al. Pretreatment Hemoglobin Adds Prognostic Information To The NCCN-IPI In Patients With Diffuse Large B-Cell Lymphoma Treated With Anthracycline-Containing Chemotherapy. Clin Epidemiol. 2019;11:987-996.
  22. Yasmeen T, Ali J, Khan K, Siddiqui N. Frequency and causes of anemia in Lymphoma patients. Pak J Med Sci. 2019;35(1):61-65.
  23. Gao R, Liang JH, Man TS, Wang L, Zhu HY, Wu W, et al. Diabetes mellitus predicts inferior survival in diffuse large B-cell lymphoma: a propensity score-matched analysis. Cancer Manag Res. 2019 9;11:2849-2870.
  24. Hong J, Lee S, Chun G, Jung JY, Park J, Ahn JY, et al. Baseline renal function as a prognostic indicator in patients with newly diagnosed diffuse large B-cell lymphoma. Blood Res. 2016;51(2):113-121.
  25. Zelenetz AD, Gordon LI, Abramson JS, Advani RH, Bartlett NL, Caimi PF, et al. NCCN Guidelines Insights: B-Cell Lymphomas, Version 3.2019. J Natl Compr Canc Netw. 2019;17(6):650-661.
  26. Soukup T, Lamb BW, Arora S, Darzi A, Sevdalis N, Green JS. Successful strategies in implementing a multidisciplinary team working in the care of patients with cancer: an overview and synthesis of the available literature. J Multidiscip Healthc. 2018;11:49-61.
  27. Ferraris AM, Giuntini P, Gaetani GF. Serum lactic dehydrogenase as a prognostic tool for non-Hodgkin lymphomas. Blood. 1979;54(4):928-932.
  28. Han S, Huang T, Li W, Liu S, Yang W, Shi Q, et al. Association Between Hypoxia-Inducible Factor-2α (HIF-2α) Expression and Colorectal Cancer and Its Prognostic Role: a Systematic Analysis. Cell Physiol Biochem. 2018;48(2):516-527.
  29. Befani C, Liakos P. The role of hypoxia-inducible factor-2 alpha in angiogenesis. J Cell Physiol. 2018;233(12):9087-9098.
  30. Ratcliffe PJ. HIF-1 and HIF-2: working alone or together in hypoxia?. J Clin Invest. 2007;117(4):862-865.
  31. Martin SK, Diamond P, Gronthos S, Peet DJ, Zannettino AC. The emerging role of hypoxia, HIF-1 and HIF-2 in multiple myeloma. Leukemia. 2011;25(10):1533-1542.
  32. Shi X, Liu X, Li X, Li Y, Lu D, Sun X, et al. Risk Stratification for Diffuse Large B-Cell Lymphoma by Integrating Interim Evaluation and International Prognostic Index: A Multicenter Retrospective Study. Front Oncol. 2021;11:754964.
  33. Bartoszewski R, Moszyńska A, Serocki M, Cabaj A, Polten A, Ochocka R, et al. Primary endothelial cell-specific regulation of hypoxia-inducible factor (HIF)-1 and HIF-2 and their target gene expression profiles during hypoxia. FASEB J. 2019;33(7):7929-7941.
  34. Imamura T, Kikuchi H, Herraiz MT, Park DY, Mizukami Y, Mino-Kenduson M, et al. HIF-1alpha and HIF-2alpha have divergent roles in colon cancer. Int J Cancer. 2009;124(4):763-71.
  35. Seifert V, Richter S, Bechmann N, Bachmann M, Ziegler CG, Pietzsch J, et al. HIF2alpha-Associated Pseudohypoxia Promotes Radioresistance in Pheochromocytoma: Insights from 3D Models. Cancers (Basel). 2021;13(3):385.
  36. Davis L, Recktenwald M, Hutt E, Fuller S, Briggs M, Goel A, et al. Targeting HIF-2α in the tumor microenvironment: Redefining the role of HIF-2α for solid cancer therapy. Cancers. 2022;14(5):1259.
  37. Gunawan RA, Widyastiti NS, Ariosta, Pratiwi R, Retnoningrum D, Ngestiningsih D, et al. The differences of lactate dehydrogenase and activin A levels among thalassemia major and non-thalassemia. Bali Medical Journal. 2021;10(3):996-1001.
  38. Darwis P, Yunir E, Kekalih A, Muradi A, Jusman SW, Yuwono HS, et al. The association between hypoxia-inducible factor 1α tissue concentration and the risk of amputation in diabetic foot ulcer patients. Bali Medical Journal. 2022;11(2):1067-1070.
  39. Pangarsa EA, Rizky D, Setiawan B, Santosa D, Haryana SM, Suharti C. Crosstalk between hypoxia and inflammation in non-Hodgkin lymphoma. Bali Medical Journal. 2022;11(3):1063-1073.

How to Cite

Adhi Pangarsa, E., Ewika Ardini, D. N. ., Rizky, D., Tandarto, K., Istiadi, H. ., Puspasari, D., Setiawan, B. ., Santosa, D. ., Hertanto Wahyu Subagio, Tri Indah Winarni, Haryana, S. M. ., & Suharti, C. . (2023). The association of Hypoxia-Inducible Factor-2α (HIF-2α) overexpression score with Germinal Center B-Cell Like (GCB) and Non-Germinal Center B-Cell Like (Non-GCB) subtypes of Diffuse Large B-cell Lymphoma (DLBCL). Bali Medical Journal, 12(3), 2456–2462. https://doi.org/10.15562/bmj.v12i3.4521
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Eko Adhi Pangarsa
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Desta Nur Ewika Ardini
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Daniel Rizky
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Kevin Tandarto
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Hermawan Istiadi
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Dik Puspasari
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Budi Setiawan
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Damai Santosa
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Hertanto Wahyu Subagio
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Tri Indah Winarni
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Sofia Mubarika Haryana
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Catharina Suharti
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