RETROSPECTIVE ANALYSIS OF GENETIC MUTATION TEST RESULTS IN PATIENTS FOLLOWED WITH POLYCYCEMIA

Öz

ABSTRACT Objective: The aim of our study is to determine breakpoints for genetic test requests in patients referred to the outpatient clinic due to polycythemia. Thus, the workload of hematology and medical genetics departments and unnecessary requests will be avoided and the cost will be reduced. Material and Methods: Our study is a retrospective cross-sectional study, including patients admitted between March 2019 and April 2021. A total of 210 patients over the age of 18 for whom genetic analysis was requested to determine the cause of polycythemia were included in the study. The information of the patients who met the research criteria was obtained retrospectively from the hospital automation system. Results: JAK2V617F mutation was found in 19 (9.09%) of 210 patients included in the study, and JAK2 exon 12 mutation was found in 1 (1.16%). Secondary polycythemia rate was 89.75%, primary polycythemia rate was 10.25%. The leukocyte count in JAK2 positive male patients and the platelet count in female patients were found to be significantly higher than in JAK2 negative patients. In general, the Hgb, Htc, creatinine and ALT values of male patients were found to be statistically significantly higher than females. In the ROC analysis for the prediction of JAK2 presence, no significant cut-off value was found for Hgb, Htc and EPO. Conclusion: We revealed that the polycythemia of patients who were requested to test for JAK2 mutation was mostly due to secondary causes. However, as a result of the ROC analysis, we saw that the Hgb and Htc cut-off values used for the JAK2 mutation request were in parallel with the limit values recommended by WHO. Therefore, it would be an effective approach to rule out secondary causes by questioning in detail before JAK2 analysis is requested. Keywords: Polycythemia, Janus Kinase 2, Polycythemia Vera

Anahtar Kelimeler

• polycythemia, janus kinase 2, polycythemia vera

Polisitemi ile Takipli Hastalarda Genetik Mutasyon Test Sonuçlarının Retrospektif Analizi

Öz

ÖZET Amaç: Çalışmamızın amacı, polisitemi nedeniyle polikliniğe yönlendirilen hastalarda genetik test istemleri için sınır değerler belirlemektir. Böylelikle hematoloji ve tıbbi genetik bölümlerinin iş yükü ile gereksiz istemlerin önüne geçilerek maliyet azaltılmış olacaktır. Gereç ve Yöntemler: Çalışmamız Mart 2019-Nisan 2021 tarihleri arasında başvuran hastalar dahil edilerek yapılan retrospektif kesitsel bir çalışmadır. Çalışmaya polisitemi nedeninin belirlenmesi için genetik analiz istenen 18 yaş üzeri 210 hasta dahil edilmiştir. Araştırma kriterlerine uygun hastaların bilgilerine hastane otomasyon sisteminden geriye dönük ulaşılmıştır. Bulgular: Çalışmaya alınan 210 hastanın 19’unda (%9,09) JAK2V617F mutasyonu, 1’inde (%1,16) JAK2 ekzon 12 mutasyonu saptanmıştır. Sekonder polisitemi oranı %89,75, primer polisitemi oranı %10,25 bulunmuştur. JAK2 pozitif erkek hastalarda lökosit sayısı ve kadın hastalarda trombosit sayısı, JAK2 negatif hastalara göre anlamlı olarak daha yüksek bulunmuştur. Genel olarak erkek hastaların Hgb, Htc, kreatinin, ALT değerleri kadınlara göre istatistiksel olarak anlamlı yüksek bulunmuştur. JAK2 varlığı tahmini açısından yapılan ROC analizinde Hgb, Htc ve EPO için anlamlı bir cut off değer bulunamamıştır. Sonuç: JAK2 mutasyon testi istenen hastaların polisitemisinin çoğunlukla sekonder nedenlerden kaynaklandığını ortaya koyduk. Ancak ROC analizi sonucunda JAK2 mutasyon istemi için kullanılan Hgb ve Htc cut off değerlerinin DSÖ tarafından önerilen sınır değerler ile paralel seyrettiğini gördük. Dolayısıyla JAK2 analizi istenmeden önce sekonder nedenlerin ayrıntılı sorgulanarak ekarte edilmesi etkin bir yaklaşım olacaktır. Anahtar Kelimeler: Polisitemi, Janus kinaz 2, Polisitemia Vera

Anahtar Kelimeler

• Polisitemi
• Polisitemia Vera
• janus kinaz 2

Kaynakça

1. 1. Mithoowani S, Laureano M, Crowther MA, Hillis CM. Investigation and management of erythrocytosis. Canadian Medical Assoiation Journal 2020; 192: E913-E918.
2. 2. Barbui T, Thiele J, Gisslinger H, Kvasnicka HM, Vannucchi AM, Guglielmelli P et al. The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion. Blood Cancer Journal 2018; 8: 15.
3. 3. Tefferi A, Guglielmelli P, Larson DR, Finke C, Wassie EA, Pieri L et al. Long- term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood 2014; 124: 2507-13.
4. 4. Bunn HF, Gu J, Huang LE, Park JW, Zhu H. Erythropoietin: a model system for studying oxygen-dependent gene regulation. The journal of experimental biology 1998; 201:1197- 201.
5. 5. Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. The New England Journal of Medicine 2007; 356: 459-68.
6. 6. Tefferi A, Rumi E, Finazzi G, Gisslinger H, Vannucchi AM, Rodeghiero F et al. Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study. Leukemia 2013; 27:1874-81.
7. 7. Tefferi A. Polycythemia vera: a comprehensive review and clinical recommendations. Mayo Clin Proceedings 2003; 78:174-94.
8. 8.Tefferi A, Spivak JL. Polycythemia vera: scientific advances and current practice. Seminars in Hematology 2005; 42: 206-20.

9. 9. Spivak JL. Narrative review: Thrombocytosis, polycythemia vera, and JAK2 mutations: The phenotypic mimicry of chronic myeloproliferation. Annals of Internal Medicine 2010; 152: 300-6.
10. 10. Maddali M, Kulkarni UP, Ravindra N, Jajodia E, Arunachalam AK, Suresh H et al. JAK2 exon 12 mutations in cases with JAK2V617F-negative polycythemia vera and primary myelofibrosis. Annals of Hematology 2020; 99: 983-989.
11. 11. Anger B, Haug U, Seidler R, Heimpel H. Polycythemia vera. A clinical study of 141 patients. Blut 1989; 59: 493-500.
12. 12. Berlin NI. Diagnosis and classification of the polycythemias. Seminars in Hematology 1975; 12: 339-51.
13. 13. Polycythemia vera: the natural history of 1213 patients followed for 20 years. Gruppo Italiano Studio Policitemia. Annals of Internal Medicine 1995; 123: 656-64.
14. 14. Crisà E, Venturino E, Passera R, Prina M, Schinco P, Borchiellini A et al. A retrospective study on 226 polycythemia vera patients: impact of median hematocrit value on clinical outcomes and survival improvement with anti-thrombotic prophylaxis and non-alkylating drugs. Annals of Hematology 2010; 89: 691-9.
15. 15. Nadeem O, Gui J, Ornstein DL. Prevalence of venous thromboembolism in patients with secondary polycythemia. Clinical and Applied Thrombosis/ Hemostasis 2013;19: 363-6.
16. 16. Lubarsky DA, Gallagher CJ, Berend JL. Secondary polycythemia does not increase the risk of perioperative hemorrhagic or thrombotic complications. Journal of Clinical Anesthesia 1991; 3: 99-103.
17. 17. Wouters HJCM, Mulder R, van Zeventer IA, Schuringa JJ, van der Klauw MM et al. Erythrocytosis in the general population: clinical characteristics and association with clonal hematopoiesis. Blood Advances 2020; 4: 6353-6363.
18. 18. Nguyen E, Szuber N, Harnois M, Busgele L, Mollica L, Assouline SE et al. Secondary erythrocytosis in phenotypically distinct from polycythemia vera but associated with comperable rates of thrombosis at diagnosis. Blood 2020; 136: 4-7.
19. 19. Ania BJ, Suman VJ, Sobell JL, Codd MB, Silverstein MN, Melton LJ. Trends in the incidence of polycythemia vera among Olmsted County, Minnesota residents, 1935-1989. American Journal of Hematology 1994; 47: 89-93.
20. 20. Finazzi G; low-dose aspirin in polycythemia (ECLAP). A prospective analysis of thrombotic events in the European collaboration study on low-dose aspirin in polycythemia (ECLAP). Pathologie Biologie 2004; 52: 285-8.
21. 21. Eyüpler Akmercan Ç. Polisitemi Vera hastalarının demografik ve klinik özelliklerinin survi ve prognoz üzerine etkisinin incelenmesi; retrospektif tek merkez deneyimi. Marmara Üniversitesi İç Hastalıkları Uzmanlık Tezi, İstanbul 2021.
22. 22. Ren Y, Fu R, Qu W, Ruan E, Wang X, Wang G et al. Clinical analysis of 70 cases of polycythemia vera. Zhonghua Yi Xue Za Zhi. 2015; 95(18):1378-81.
23. 23. Bai J, Shao Z, Jing L, Liu H, Shi J, Zhao M et al. Clinical analysis of 185 patients with polycythemia vera. Zhonghua Xue Ye Xue Za Zhi. 2002; 23: 578-80.
24. 24. Brodmann S, Passweg JR, Gratwohl A, Tichelli A, Skoda RC. Myeloproliferative disorders: complications, survival and causes of death. Annals of Hematology 2000; 79: 312-8.
25. 25. Gangat N, Strand J, Li CY, Wu W, Pardanani A, Tefferi A. Leucocytosis in polycythaemia vera predicts both inferior survival and leukaemic transformation. British Journal of Haematology 2007; 138: 354-8.
26. 26. Landolfi R, Di Gennaro L, Barbui T, De Stefano V, Finazzi G, Marfisi R et al. Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera. Blood 2007; 109: 2446-52.
27. 27. Murphy WG. The sex difference in haemoglobin levels in adults - mechanisms, causes, and consequences. Blood Reviews 2014; 28: 41-7.
28. 28. Quinn PG, Johnston DE. Detection of chronic liver disease: costs and benefits. The Gastroenterologist 1997; 5: 58-77.