MOLECULAR PROFILING OF BCR-ABL NEGATIVE MYELOPROLIFERATIVE  NEOPLASMS, GOING BEYOND DRIVER MUTATIONS, SINGLE CENTER EXPERIENCE

Marija Popova Labachevska; Irina Panova Stavridis; Sanja Trajkova; Nevenka Ridova; Marija Staninova; Simona Stojanovska Jakimovska; Aleksandra Pivkova; Zlate Stojanoski; Velimir Stojkoski

Marija Popova Labachevska University Clinic for Hematology, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, North Macedonia
Irina Panova Stavridis University Clinic for Hematology, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, North Macedonia
Sanja Trajkova University Clinic for Hematology, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, North Macedonia
Nevenka Ridova University Clinic for Hematology, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, North Macedonia
Marija Staninova Center for Biomolecular Pharmaceutical Analyses, Faculty of Pharmacy, Ss. Cyril and Methodius University in Skopje, North Macedonia
Simona Stojanovska Jakimovska University Clinic for Hematology, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, North Macedonia
Aleksandra Pivkova University Clinic for Hematology, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, North Macedonia
Zlate Stojanoski University Clinic for Hematology, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, North Macedonia
Velimir Stojkoski Food Institute, Faculty of Veterinary Medicine,Ss Cyril and Methodius University in Skopje, North Macedonia

Abstract

The classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) comprise essential thrombocythemia (ET), primary myelofibrosis (PMF), and polycythemia vera (PV). Major complications responsible for disease-related mortality are thromboembolic and hemorrhagic events, and in a subset of MPN patients, disease transformation to secondary acute myeloid leukaemia or PMF can occur. Besides well-established driver mutations, further molecular studies, revealed novel somatic mutations i.e. non-driver mutations, whose occurrence may precede or follow the acquisition of driver mutations and can contribute in phenotypic variability, and disease progression. In order to justify these observations, we examined the mutational profile of 78 patients with MPNs using next-generation sequencing for the detection of non-driver mutations in correlation with clinical presentation. Somatic driver mutations were detected in 64 (78%) while 14 (17, 9%) were triple negative MPN cases. Most prevalent driver mutation was JAK2V617F mutation 54 (69, 2%), followed by CALR (10, 2%) and MPL in two (2, 5%). Fourteen (17, 9%) were triple negative cases. Mutations in ASXL1 gene were detected in one patient with ET and one with PMF, while mutations in TET2 gene were detected in three ET, two PV and two PMF patients, all of them JAK2V617F positive. TP53 mutation was present in three patients, one with PV and two with ET. More than two non-driver mutations were seen in one patient with prefibrotic i.e hypercellular phase of myelofibrosis. Larger studies are needed to conclude whether the landscape of non-driver mutations differs among cohorts and how their presence affects clinical presentation.

Keywords: myeloproliferative neoplasms, JAK2V617F mutation, non-driver mutations.

https://doi.org/10.55302/JMS236108pl

References

1. K. Zoi, N. Cross. Genomics of myeloproliferative neoplasms. Journal of Clinical Oncology, 35 (2017), pp. 947-954.
2. Iurlo, D. Cattaneo, U. Gianelli, Blast transformation in myeloproliferative neoplasms: risk factors, biological findings, and targeted therapeutic options. Int J Mol Sci, 20 (2019), p.1839.
3. Kremyanskaya M, Mascarenhas J, Hoffman R. Why does my patient have erythrocytosis? Hematol Oncol Clin North Am. 2012 Apr; 26(2):267-83.
4. Santhosh-Kumar CR, Yohannan MD, Higgy KE, al-Mashhadani SA. Thrombocytosis in adults: analysis of 777 patients. J Intern Med. 1991 Jun; 229(6):493-5.
5. Barbui T, Thiele J, Gisslinger H, Kvasnicka HM, Vannucchi AM, Guglielmelli P, Orazi A, Tefferi A. The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion. Blood Cancer Journal. 2018 Feb 9; 8(2):15.
6. Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR, Futreal PA, Erber WN, McMullin MF, Harrison CN, Warren AJ, Gilliland DG, Lodish HF, Green AR. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med. 2007 Feb 01; 356(5):459-68.
7. Vainchenker W, Kralovics R. Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. Blood. 2017 Feb 09; 129(6):667-679.
8. Shammo JM, Stein BL. Mutations in MPNs: prognostic implications, window to biology, and impact on treatment decisions. Hematology Am Soc Hematol Educ Program. 2016 Dec 2; 2016(1):552-560.
9. Vannucchi AM, Lasho TL, Guglielmelli P, Biamonte F, Pardanani A, Pereira A, Finke C, Score J, Gangat N, Mannarelli C, Ketterling RP, Rotunno G, Knudson RA, Susini MC, Laborde RR, Spolverini A, Pancrazzi A, Pieri L, Manfredini R, Tagliafico E, Zini R, Jones A, Zoi K, Reiter A, Duncombe A, Pietra D, Rumi E, Cervantes F, Barosi G, Cazzola M, Cross NC, Tefferi A. Mutations and prognosis in primary myelofibrosis. Leukemia. 2013 Sep; 27(9):1861-9.
10. Jovanovic JV, Ivey A, Vannucchi AM, Lippert E, Oppliger Leibundgut E,et al.Establishing optimal quantitative-polymerase chain reaction assays for routine diagnosis and tracking of minimal residual disease in JAK2-V617F-associated myeloproliferative neoplasms: A joint European LeukemiaNet MPN&MPNr-EuroNet (COST action BM0902) study. Leukemia. 2013; 27(10): 2032-2039.
11. Mesa RA, Passamonti F. Individualizing Care for Patients With Myeloproliferative Neoplasms: Integrating Genetics, Evolving Therapies, and Patient-Specific Disease Burden. Am Soc Clin Oncol Educ Book. 2016; 35:e324-35.
12. Patriarca A, Colaizzo D, Tiscia G, Spadano R, Di Zacomo S, Spadano A, Villanova I, Margaglione M, Grandone E, Dragani A. TET2 mutations in Ph-negative myeloproliferative neoplasms: identification of three novel mutations and relationship with clinical and laboratory findings. Biomed Res Int. 2013; 2013:929840.
13. Li B, Gale RP, Xu Z, Qin T, Song Z, Zhang P, Bai J, Zhang L, Zhang Y, Liu J, Huang G, Xiao Z. Non-driver mutations in myeloproliferative neoplasm-associated myelofibrosis. J Hematol Oncol. 2017 May 2; 10(1):99.