Prevalence of the Janus kinase 2 V617F mutation in Philadelphia‑negative myeloproliferative neoplasms in a Portuguese population

Azevedo,Ana Paula; Azevedo,Ana Paula; Silva,Susana   N.; Silva,Susana   N.; Reichert,Alice; Reichert,Alice; Lima,Fernando; Lima,Fernando; Júnior,Esmeraldina; Júnior,Esmeraldina; Rueff,José; Rueff,José

doi:10.3892/br.2017.977

Prevalence of the Janus kinase 2 V617F mutation in Philadelphia‑negative myeloproliferative neoplasms in a Portuguese population

Authors:
- Ana Paula Azevedo
- Susana N. Silva
- Alice Reichert
- Fernando Lima
- Esmeraldina Júnior
- José Rueff
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Affiliations: Centre for Toxicogenomics and Human Health (ToxOmics), Genetics, Oncology and Human Toxicology, NOVA Medical School, Faculty of Medical Sciences, NOVA University of Lisbon, 1169‑056 Lisbon, Portugal, Department of Clinical Hematology, Hospital of São Francisco Xavier, West Lisbon Hospital Centre, 1449‑005 Lisbon, Portugal, Department of Clinical Pathology, Hospital of São Francisco Xavier, West Lisbon Hospital Centre, 1449‑005 Lisbon, Portugal
Published online on: September 5, 2017 https://doi.org/10.3892/br.2017.977
Pages: 370-376

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Abstract

Myeloproliferative neoplasms (MPNs) result from the malignant transformation of a hematopoietic stem‑cell (HSC), leading to abnormal amplification and proliferation of myeloid lineages. Identification of the Janus kinase 2 (JAK2) V617F mutation developed the knowledge of Philadelphia‑negative (PN)‑MPNs, contributing to and influencing the definition of the phenotype and prognostic impact. Considering the lack of Portuguese epidemiological data, the present study intends to characterize the prevalence of the JAK2 mutation in a PN‑MPN versus a control Portuguese population. Caucasian Portuguese PN‑MPN patients (n=133) and 281 matched control subjects were investigated. No significant differences were identified between the case and control groups concerning age distribution or smoking habits. Pathology distribution was as follows: 60.2% with essential thrombocythemia (ET), 29.3% with polycythemia vera (PV) and 10.5% with primary myelofibrosis (PMF). A total of 75.0% of patients were positive for the presence of the JAK2 V617F mutation. In addition, the prevalence of PV was 87.2%, ET was 73.4% and PMF was 50.0%. The JAK2 V617F mutation is observed in various MPN phenotypes, and has an increased incidence in ET patients and a decreased incidence in PV patients. These data may contribute to improving the knowledge of the pathophysiology of these disorders, and to a more rational and efficient selection of therapeutic strategies to be adopted, notably because most of the patients are JAK2 V617F negative.

References

1	Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J and Vardiman JW: WHO Classification of Tumours of Haematopioetic and Lymphoid Tissues. World Health Organization; Lyon: 2008
2	Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M and Vardiman JW: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 127:2391–2405. 2016. View Article : Google Scholar : PubMed/NCBI
3	Titmarsh GJ, Duncombe AS, McMullin MF, O'Rorke M, Mesa R, De Vocht F, Horan S, Fritschi L, Clarke M and Anderson LA: How common are myeloproliferative neoplasms? A systematic review and meta-analysis. Am J Hematol. 89:581–587. 2014. View Article : Google Scholar : PubMed/NCBI
4	Moulard O, Mehta J, Fryzek J, Olivares R, Iqbal U and Mesa RA: Epidemiology of myelofibrosis, essential thrombocythemia, and polycythemia vera in the European Union. Eur J Haematol. 92:289–297. 2014. View Article : Google Scholar : PubMed/NCBI
5	Cross NC: Genetic and epigenetic complexity in myeloproliferative neoplasms. Hematology (Am Soc Hematol Educ Program). 2011:208–214. 2011.PubMed/NCBI
6	Tefferi A and Pardanani A: Myeloproliferative Neoplasms: A Contemporary Review. JAMA Oncol. 1:97–105. 2015. View Article : Google Scholar : PubMed/NCBI
7	Duletić AN, Dekanić A, Hadzisejdić I, Kusen I, Matusan-Ilijas K, Grohovac D, Grahovac B and Jonjić N: JAK2-v617F mutation is associated with clinical and laboratory features of myeloproliferative neoplasms. Coll Antropol. 36:859–865. 2012.PubMed/NCBI
8	Tefferi A and Vardiman JW: Classification and diagnosis of myeloproliferative neoplasms: The 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia. 22:14–22. 2008. View Article : Google Scholar : PubMed/NCBI
9	James C, Ugo V, Le Couédic JP, Staerk J, Delhommeau F, Lacout C, Garçon L, Raslova H, Berger R, Bennaceur-Griscelli A, et al: A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 434:1144–1148. 2005. View Article : Google Scholar : PubMed/NCBI
10	Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola M and Skoda RC: A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 352:1779–1790. 2005. View Article : Google Scholar : PubMed/NCBI
11	Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, Boggon TJ, Wlodarska I, Clark JJ, Moore S, et al: Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 7:387–397. 2005. View Article : Google Scholar : PubMed/NCBI
12	Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, Vassiliou GS, Bench AJ, Boyd EM and Curtin N: Cancer Genome Project: Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 365:1054–1061. 2005. View Article : Google Scholar : PubMed/NCBI
13	Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR, Futreal PA, Erber WN, McMullin MF, Harrison CN, et al: JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med. 356:459–468. 2007. View Article : Google Scholar : PubMed/NCBI
14	Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC, Avezov E, Li J, Kollmann K, Kent DG, et al: Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 369:2391–2405. 2013. View Article : Google Scholar : PubMed/NCBI
15	Levine RL: Mechanisms of mutations in myeloproliferative neoplasms. Best Pract Res Clin Haematol. 22:489–494. 2009. View Article : Google Scholar : PubMed/NCBI
16	Hinds DA, Barnholt KE, Mesa RA, Kiefer AK, Do CB, Eriksson N, Mountain JL, Francke U, Tung JY, Nguyen HM, et al: Germ line variants predispose to both JAK2 V617F clonal hematopoiesis and myeloproliferative neoplasms. Blood. 128:1121–1128. 2016. View Article : Google Scholar : PubMed/NCBI
17	Cazzola M and Kralovics R: From Janus kinase 2 to calreticulin: The clinically relevant genomic landscape of myeloproliferative neoplasms. Blood. 123:3714–3719. 2014. View Article : Google Scholar : PubMed/NCBI
18	Oh ST and Gotlib J: JAK2 V617F and beyond: Role of genetics and aberrant signaling in the pathogenesis of myeloproliferative neoplasms. Expert Rev Hematol. 3:323–337. 2010. View Article : Google Scholar : PubMed/NCBI
19	Bolufer P, Barragan E, Collado M, Cervera J, López JA and Sanz MA: Influence of genetic polymorphisms on the risk of developing leukemia and on disease progression. Leuk Res. 30:1471–1491. 2006. View Article : Google Scholar : PubMed/NCBI
20	Delhommeau F, Jeziorowska D, Marzac C and Casadevall N: Molecular aspects of myeloproliferative neoplasms. Int J Hematol. 91:165–173. 2010. View Article : Google Scholar : PubMed/NCBI
21	Beer PA, Delhommeau F, LeCouédic JP, Dawson MA, Chen E, Bareford D, Kusec R, McMullin MF, Harrison CN, Vannucchi AM, et al: Two routes to leukemic transformation after a JAK2 mutation-positive myeloproliferative neoplasm. Blood. 115:2891–2900. 2010. View Article : Google Scholar : PubMed/NCBI
22	Kilpivaara O and Levine RL: JAK2 and MPL mutations in myeloproliferative neoplasms: Discovery and science. Leukemia. 22:1813–1817. 2008. View Article : Google Scholar : PubMed/NCBI
23	Björkholm M, Hultcrantz M and Derolf ÅR: Leukemic transformation in myeloproliferative neoplasms: Therapy-related or unrelated? Best Pract Res Clin Haematol. 27:141–153. 2014. View Article : Google Scholar : PubMed/NCBI
24	Rueff J and Rodrigues AS: Cancer Drug Resistance: A Brief Overview from a Genetic Viewpoint. Methods Mol Biol. 1395:1–18. 2016. View Article : Google Scholar : PubMed/NCBI
25	Rice KL, Lin X, Wolniak K, Ebert BL, Berkofsky-Fessler W, Buzzai M, Sun Y, Xi C, Elkin P, Levine R, et al: Analysis of genomic aberrations and gene expression profiling identifies novel lesions and pathways in myeloproliferative neoplasms. Blood Cancer J. 1:e402011. View Article : Google Scholar : PubMed/NCBI
26	Campregher PV, Santos FP, Perini GF and Hamerschlak N: Molecular biology of Philadelphia-negative myeloproliferative neoplasms. Rev Bras Hematol Hemoter. 34:150–155. 2012. View Article : Google Scholar : PubMed/NCBI
27	Ebid GT, Ghareeb M, Salaheldin O and Kamel MM: Prevalence of the frequency of JAK2 (V617F) mutation in different myeloproliferative disorders in Egyptian patients. Int J Clin Exp Pathol. 8:11555–11559. 2015.PubMed/NCBI
28	Jatiani SS, Baker SJ, Silverman LR and Reddy EP: Jak/STAT pathways in cytokine signaling and myeloproliferative disorders: Approaches for targeted therapies. Genes Cancer. 1:979–993. 2010. View Article : Google Scholar : PubMed/NCBI
29	Anand S, Stedham F, Beer P, Gudgin E, Ortmann CA, Bench A, Erber W, Green AR and Huntly BJ: Effects of the JAK2 mutation on the hematopoietic stem and progenitor compartment in human myeloproliferative neoplasms. Blood. 118:177–181. 2011. View Article : Google Scholar : PubMed/NCBI
30	Reuther GW: Myeloproliferative Neoplasms: Molecular Drivers and Therapeutics. Prog Mol Biol Transl Sci. 144:437–484. 2016. View Article : Google Scholar : PubMed/NCBI
31	Steensma DP, McClure RF, Karp JE, Tefferi A, Lasho TL, Powell HL, DeWald GW and Kaufmann SH: JAK2 V617F is a rare finding in de novo acute myeloid leukemia, but STAT3 activation is common and remains unexplained. Leukemia. 20:971–978. 2006. View Article : Google Scholar : PubMed/NCBI
32	Green DR and Llambi F: Cell Death Signaling. Cold Spring Harb Perspect Biol. 7:72015. View Article : Google Scholar
33	Chen E and Mullally A: How does JAK2V617F contribute to the pathogenesis of myeloproliferative neoplasms? Hematology (Am Soc Hematol Educ Program). 2014:268–276. 2014.PubMed/NCBI
34	Godfrey AL, Chen E, Massie CE, Silber Y, Pagano F, Bellosillo B, Guglielmelli P, Harrison CN, Reilly JT, Stegelmann F, et al: STAT1 activation in association with JAK2 exon 12 mutations. Haematologica. 101:e15–e19. 2016. View Article : Google Scholar : PubMed/NCBI
35	Passamonti F, Elena C, Schnittger S, Skoda RC, Green AR, Girodon F, Kiladjian JJ, McMullin MF, Ruggeri M, Besses C, et al: Molecular and clinical features of the myeloproliferative neoplasm associated with JAK2 exon 12 mutations. Blood. 117:2813–2816. 2011. View Article : Google Scholar : PubMed/NCBI
36	Nielsen C, Bojesen SE, Nordestgaard BG, Kofoed KF and Birgens HS: JAK2V617F somatic mutation in the general population: Myeloproliferative neoplasm development and progression rate. Haematologica. 99:1448–1455. 2014. View Article : Google Scholar : PubMed/NCBI
37	Ha JS, Kim YK, Jung SI, Jung HR and Chung IS: Correlations between Janus kinase 2 V617F allele burdens and clinicohematologic parameters in myeloproliferative neoplasms. Ann Lab Med. 32:385–391. 2012. View Article : Google Scholar : PubMed/NCBI
38	Larsen TS, Pallisgaard N, Møller MB and Hasselbalch HC: The JAK2 V617F allele burden in essential thrombocythemia, polycythemia vera and primary myelofibrosis - impact on disease phenotype. Eur J Haematol. 79:508–515. 2007. View Article : Google Scholar : PubMed/NCBI
39	Barbui T, Vannucchi AM, Buxhofer-Ausch V, De Stefano V, Betti S, Rambaldi A, Rumi E, Ruggeri M, Rodeghiero F, Randi ML, et al: Practice-relevant revision of IPSET-thrombosis based on 1019 patients with WHO-defined essential thrombocythemia. Blood Cancer J. 5:e3692015. View Article : Google Scholar : PubMed/NCBI
40	Vannucchi AM, Pieri L and Guglielmelli P: JAK2 Allele Burden in the Myeloproliferative Neoplasms: Effects on Phenotype, Prognosis and Change with Treatment. Ther Adv Hematol. 2:21–32. 2011. View Article : Google Scholar : PubMed/NCBI
41	Guglielmelli P, Lasho TL, Rotunno G, Score J, Mannarelli C, Pancrazzi A, Biamonte F, Pardanani A, Zoi K, Reiter A, et al: The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: An international study of 797 patients. Leukemia. 28:1804–1810. 2014. View Article : Google Scholar : PubMed/NCBI
42	Vainchenker W and Constantinescu SN: JAK/STAT signaling in hematological malignancies. Oncogene. 32:2601–2613. 2013. View Article : Google Scholar : PubMed/NCBI
43	Thomas SJ, Snowden JA, Zeidler MP and Danson SJ: The role of JAK/STAT signalling in the pathogenesis, prognosis and treatment of solid tumours. Br J Cancer. 113:365–371. 2015. View Article : Google Scholar : PubMed/NCBI
44	Nielsen C, Birgens HS, Nordestgaard BG, Kjaer L and Bojesen SE: The JAK2 V617F somatic mutation, mortality and cancer risk in the general population. Haematologica. 96:450–453. 2011. View Article : Google Scholar : PubMed/NCBI
45	Mambet C, Matei L, Necula LG and Diaconu CC: A link between the driver mutations and dysregulated apoptosis in BCR-ABL1 negative myeloproliferative neoplasms. J Immunoassay Immunochem. 37:331–345. 2016. View Article : Google Scholar : PubMed/NCBI
46	Tefferi A and Barbui T: Polycythemia vera and essential thrombocythemia: 2017 update on diagnosis, risk-stratification, and management. Am J Hematol. 92:94–108. 2017. View Article : Google Scholar : PubMed/NCBI
47	Tefferi A: Myeloproliferative neoplasms: A decade of discoveries and treatment advances. Am J Hematol. 91:50–58. 2016. View Article : Google Scholar : PubMed/NCBI
48	Hobbs GS, Rozelle S and Mullally A: The Development and Use of Janus Kinase 2 Inhibitors for the Treatment of Myeloproliferative Neoplasms. Hematol Oncol Clin North Am. 31:613–626. 2017. View Article : Google Scholar : PubMed/NCBI
49	Vannucchi AM and Harrison CN: Emerging treatments for classical myeloproliferative neoplasms. Blood. 129:693–703. 2017. View Article : Google Scholar : PubMed/NCBI
50	Stahl M and Zeidan AM: Management of myelofibrosis: JAK inhibition and beyond. Expert Rev Hematol. 10:459–477. 2017. View Article : Google Scholar : PubMed/NCBI
51	Silva SN, Moita R, Azevedo AP, Gouveia R, Manita I, Pina JE, Rueff J and Gaspar J: Menopausal age and XRCC1 gene polymorphisms: Role in breast cancer risk. Cancer Detect Prev. 31:303–309. 2007. View Article : Google Scholar : PubMed/NCBI
52	Bastos HN, Antão MR, Silva SN, Azevedo AP, Manita I, Teixeira V, Pina JE, Gil OM, Ferreira TC, Limbert E, et al: Association of polymorphisms in genes of the homologous recombination DNA repair pathway and thyroid cancer risk. Thyroid. 19:1067–1075. 2009. View Article : Google Scholar : PubMed/NCBI
53	Conde J, Silva SN, Azevedo AP, Teixeira V, Pina JE, Rueff J and Gaspar JF: Association of common variants in mismatch repair genes and breast cancer susceptibility: A multigene study. BMC Cancer. 9:3442009. View Article : Google Scholar : PubMed/NCBI
54	Gomes BC, Silva SN, Azevedo AP, Manita I, Gil OM, Ferreira TC, Limbert E, Rueff J and Gaspar JF: The role of common variants of non-homologous end-joining repair genes XRCC4, LIG4 and Ku80 in thyroid cancer risk. Oncol Rep. 24:1079–1085. 2010.PubMed/NCBI
55	Silva SN, Azevedo AP, Teixeira V, Pina JE, Rueff J and Gaspar JF: The role of GSTA2 polymorphisms and haplotypes in breast cancer susceptibility: A case-control study in the Portuguese population. Oncol Rep. 22:593–598. 2009.PubMed/NCBI
56	Solé X, Guinó E, Valls J, Iniesta R and Moreno V: SNPStats: A web tool for the analysis of association studies. Bioinformatics. 22:1928–1929. 2006. View Article : Google Scholar : PubMed/NCBI
57	Rumi E and Cazzola M: Diagnosis, risk stratification, and response evaluation in classical myeloproliferative neoplasms. Blood. 129:680–692. 2017. View Article : Google Scholar : PubMed/NCBI
58	Jones AV, Kreil S, Zoi K, Waghorn K, Curtis C, Zhang L, Score J, Seear R, Chase AJ, Grand FH, et al: Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood. 106:2162–2168. 2005. View Article : Google Scholar : PubMed/NCBI
59	Lundberg P, Takizawa H, Kubovcakova L, Guo G, Hao-Shen H, Dirnhofer S, Orkin SH, Manz MG and Skoda RC: Myeloproliferative neoplasms can be initiated from a single hematopoietic stem cell expressing JAK2-V617F. J Exp Med. 211:2213–2230. 2014. View Article : Google Scholar : PubMed/NCBI
60	Butcher CM, Hahn U, To LB, Gecz J, Wilkins EJ, Scott HS, Bardy PG and D'Andrea RJ: Two novel JAK2 exon 12 mutations in JAK2V617F-negative polycythaemia vera patients. Leukemia. 22:870–873. 2008. View Article : Google Scholar : PubMed/NCBI
61	Park CH, Lee KO, Jang JH, Jung CW, Kim JW, Kim SH and Kim HJ: High frequency of JAK2 exon 12 mutations in Korean patients with polycythaemia vera: Novel mutations and clinical significance. J Clin Pathol. 69:737–741. 2016. View Article : Google Scholar : PubMed/NCBI
62	Passamonti F, Rumi E, Pietra D, Elena C, Boveri E, Arcaini L, Roncoroni E, Astori C, Merli M, Boggi S, et al: A prospective study of 338 patients with polycythemia vera: The impact of JAK2 (V617F) allele burden and leukocytosis on fibrotic or leukemic disease transformation and vascular complications. Leukemia. 24:1574–1579. 2010. View Article : Google Scholar : PubMed/NCBI
63	Rumi E, Pietra D, Ferretti V, Klampfl T, Harutyunyan AS, Milosevic JD, Them NC, Berg T, Elena C, Casetti IC, et al: Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative Investigators: JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood. 123:1544–1551. 2014. View Article : Google Scholar : PubMed/NCBI
64	Scott LM: The JAK2 exon 12 mutations: A comprehensive review. Am J Hematol. 86:668–676. 2011. View Article : Google Scholar : PubMed/NCBI
65	Scott LM, Beer PA, Bench AJ, Erber WN and Green AR: Prevalance of JAK2 V617F and exon 12 mutations in polycythaemia vera. Br J Haematol. 139:511–512. 2007. View Article : Google Scholar : PubMed/NCBI
66	Pardanani A, Lasho TL, Finke C, Hanson CA and Tefferi A: Prevalence and clinicopathologic correlates of JAK2 exon 12 mutations in JAK2V617F-negative polycythemia vera. Leukemia. 21:1960–1963. 2007. View Article : Google Scholar : PubMed/NCBI
67	Azevedo AP, Silva SN, De Lima JP, Reichert A, Lima F, Júnior E and Rueff J: DNA repair genes polymorphisms and genetic susceptibility to Philadelphia-negative myeloproliferative neoplasms in a Portuguese population: The role of base excision repair genes polymorphisms. Oncol Lett. 13:4641–4650. 2017.PubMed/NCBI
68	Lindholm Sørensen A and Hasselbalch HC: Smoking and philadelphia-negative chronic myeloproliferative neoplasms. Eur J Haematol. 97:63–69. 2015. View Article : Google Scholar : PubMed/NCBI
69	Hasselbalch HC: Smoking as a contributing factor for development of polycythemia vera and related neoplasms. Leuk Res. 15:30373–30378. 2015.