Advertisement

International Journal of Hematology

, Volume 110, Issue 6, pp 690–698 | Cite as

TERT and JAK2 polymorphisms define genetic predisposition to myeloproliferative neoplasms in Japanese patients

  • Masafumi Matsuguma
  • Toshiaki YujiriEmail author
  • Kaoru Yamamoto
  • Yasuko Kajimura
  • Yoshihiro Tokunaga
  • Mayumi Tanaka
  • Yoshinori Tanaka
  • Yukinori Nakamura
  • Yukio Tanizawa
Original Article

Abstract

Myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are often characterized by specific somatic mutations in any of the three genes: JAK2, CALR, or MPL. A single nucleotide polymorphism (SNP), rs2736100, in the reverse transcriptase gene (TERT) and a germline JAK2 46/1 haplotype have been associated with MPNs in North American and European patients. We examined 201 Japanese MPN patients, including 52 with PV, 131 with ET, and 18 with PMF, as well as 366 control individuals for TERT rs2736100 and JAK2 rs10974944, a tagging SNP of the 46/1 haplotype. Furthermore, correlations between the JAK2 V617F allele burden at diagnosis and TERT rs2736100 or JAK2 rs10974944 were evaluated using a digital PCR assay for accurate quantitation. The JAK2 46/1 haplotype, but not the TERT rs2736100 SNP, was correlated to the JAK2 V617F mutant allele burden in JAK2 V617F-positive MPN patients. In conclusion, we demonstrated that both TERT rs2736100_C and JAK2 46/1 haplotype are predisposing factors for MPNs in Japanese patients. While TERT rs2736100_C tended to have a more general, non-specific effect on all MPNs, the JAK2 46/1 haplotype was essentially predisposed to the JAK2 V617F-positive MPNs.

Keywords

Myeloproliferative neoplasms JAK2 TERT Single nucleotide polymorphisms Digital PCR 

Notes

Acknowledgements

The authors would like to thank Drs. Kenji Shinohara, Yoichi Azuno, Masatoshi Tsuru, Shinobu Imoto, Toru Takahashi, Ryouhei Nawata, Takayuki Tominaga, Koji Yamashita, Kumiko Matsui, Akiko Sugiyama, and Munehiro Suzukawa for patient enrollment. In addition, we would like to thank Dr. Yutaka Suehiro, Ms. Naoko Okayama, Ms. Yukiko Nakahara, Mr. Akihiro Morishige, and Ms. Sayuri Hayashi for their technical support during the study.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The study was approved by the institutional ethics committee of the Graduate School of Medicine, Yamaguchi University Hospital and participating affiliated hospitals.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Michiels JJ, Berneman Z, Schroyens W, De Raeve H. Changing concepts of diagnostic criteria of myeloproliferative disorders and the molecular etiology and classification of myeloproliferative neoplasms: from Dameshek 1950 to Vainchenker 2005 and beyond. Acta Haematol. 2015;133:36–51.CrossRefGoogle Scholar
  2. 2.
    Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405.CrossRefGoogle Scholar
  3. 3.
    Jones AV, Chase A, Silver RT, Oscier D, Zoi K, Wang YL, et al. JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms. Nat Genet. 2009;41:446–9.CrossRefGoogle Scholar
  4. 4.
    Kilpivaara O, Mukherjee S, Schram AM, Wadleigh M, Mullally A, Ebert BL, et al. A germline JAK2 SNP is associated with predisposition to the development of JAK2(V617F)-positive myeloproliferative neoplasms. Nat Genet. 2009;41:455–9.CrossRefGoogle Scholar
  5. 5.
    Olcaydu D, Harutyunyan A, Jager R, Berg T, Gisslinger B, Pabinger I, et al. A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms. Nat Genet. 2009;41:450–4.CrossRefGoogle Scholar
  6. 6.
    Zhang X, Hu T, Wu Z, Kang Z, Liu W, Guan M. The JAK2 46/1 haplotype is a risk factor for myeloproliferative neoplasms in Chinese patients. Int J Hematol. 2012;96:611–6.CrossRefGoogle Scholar
  7. 7.
    Tanaka M, Yujiri T, Ito S, Okayama N, Takahashi T, Shinohara K, et al. JAK2 46/1 haplotype is associated with JAK2 V617F-positive myeloproliferative neoplasms in Japanese patients. Int J Hematol. 2013;97:409–13.CrossRefGoogle Scholar
  8. 8.
    Oddsson A, Kristinsson SY, Helgason H, Gudbjartsson DF, Masson G, Sigurdsson A, et al. The germline sequence variant rs2736100_C in TERT associates with myeloproliferative neoplasms. Leukemia. 2014;28:1371–4.CrossRefGoogle Scholar
  9. 9.
    Tapper W, Jones AV, Kralovics R, Harutyunyan AS, Zoi K, Leung W, et al. Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms. Nat Commun. 2015;6:6691.CrossRefGoogle Scholar
  10. 10.
    Vannucchi AM, Pieri L, Guglielmelli P. JAK2 allele burden in the myeloproliferative neoplasms: effects on phenotype, prognosis and change with treatment. Ther Adv Hematol. 2011;2:21–322.CrossRefGoogle Scholar
  11. 11.
    Misawa K, Yasuda H, Araki M, Ochiai T, Morishita S, Shirane S, et al. Mutational subtypes of JAK2 and CALR correlate with different clinical features in Japanese patients with myeloproliferative neoplasms. Int J Hematol. 2018;107:673–80.CrossRefGoogle Scholar
  12. 12.
    Link-Lenczowska D, Pallisgaard N, Cordua S, Zawada M, Czekalska S, Krochmalczyk D, et al. A comparison of qPCR and ddPCR used for quantification of the JAK2 V617F allele burden in Ph negative MPNs. Ann Hematol. 2018;97:2299–308.CrossRefGoogle Scholar
  13. 13.
    Pardanani AD, Levine RL, Lasho T, Pikman Y, Mesa RA, Wadleigh M, et al. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood. 2006;108:3472–6.CrossRefGoogle Scholar
  14. 14.
    Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369:2391–405.CrossRefGoogle Scholar
  15. 15.
    Kim SY, Im K, Park SN, Kwon J, Kim JA, Lee DS. CALR, JAK2, and MPL mutation profiles in patients with four different subtypes of myeloproliferative neoplasms: primary myelofibrosis, essential thrombocythemia, polycythemia vera, and myeloproliferative neoplasm, unclassifiable. Am J Clin Pathol. 2015;143:635–44.CrossRefGoogle Scholar
  16. 16.
    Kinz E, Leiherer A, Lang AH, Drexel H, Muendlein A. Accurate quantitation of JAK2 V617F allele burden by array-based digital PCR. Int J Lab Hematol. 2015;37:217–24.CrossRefGoogle Scholar
  17. 17.
    Kanda Y. Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant. 2013;48:452–8.CrossRefGoogle Scholar
  18. 18.
    Matakidou A, Hamel N, Popat S, Henderson K, Kantemiroff T, Harmer C, et al. Risk of non-medullary thyroid cancer influenced by polymorphic variation in the thyroglobulin gene. Carcinogenesis. 2004;25:369–73.CrossRefGoogle Scholar
  19. 19.
    Trifa AP, Banescu C, Tevet M, Bojan A, Dima D, Urian L, et al. TERT rs2736100 A%3eC SNP and JAK2 46/1 haplotype significantly contribute to the occurrence of JAK2 V617F and CALR mutated myeloproliferative neoplasms—a multicentric study on 529 patients. Br J Haematol. 2016;174:218–26.CrossRefGoogle Scholar
  20. 20.
    Bojesen SE. Telomeres and human health. J Intern Med. 2013;274:399–413.CrossRefGoogle Scholar
  21. 21.
    Bojesen SE, Pooley KA, Johnatty SE, Beesley J, Michailidou K, Tyrer JP, et al. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer. Nat Genet. 2013;45:371–84.CrossRefGoogle Scholar
  22. 22.
    McKay JD, Hung RJ, Gaborieau V, Boffetta P, Chabrier A, Byrnes G, et al. Lung cancer susceptibility locus at 5p15.33. Nat Genet. 2008;40:1404–6.CrossRefGoogle Scholar
  23. 23.
    Wang Y, Broderick P, Webb E, Wu X, Vijayakrishnan J, Matakidou A, et al. Common 5p15.33 and 6p21.33 variants influence lung cancer risk. Nat Genet. 2008;40:1407–9.CrossRefGoogle Scholar
  24. 24.
    Shete S, Hosking FJ, Robertson LB, Dobbins SE, Sanson M, Malmer B, et al. Genome-wide association study identifies five susceptibility loci for glioma. Nat Genet. 2009;41:899–904.CrossRefGoogle Scholar
  25. 25.
    Kamatani Y, Matsuda K, Okada Y, Kubo M, Hosono N, Daigo Y, et al. Genome-wide association study of hematological and biochemical traits in a Japanese population. Nat Genet. 2010;42:210–5.CrossRefGoogle Scholar
  26. 26.
    Trifa AP, Cucuianu A, Petrov L, Urian L, Militaru MS, Dima D, et al. The G allele of the JAK2 rs10974944 SNP, part of JAK2 46/1 haplotype, is strongly associated with JAK2 V617F-positive myeloproliferative neoplasms. Ann Hematol. 2010;89:979–83.CrossRefGoogle Scholar
  27. 27.
    Gau JP, Chen CC, Chou YS, Liu CJ, Yu YB, Hsiao LT, et al. No increase of JAK2 46/1 haplotype frequency in essential thrombocythemia with CALR mutations: Functional effect of the haplotype limited to allele with JAK2V617F mutation but not CALR mutation. Blood Cells Mol Dis. 2015;55:36–9.CrossRefGoogle Scholar
  28. 28.
    Trifa AP, Banescu C, Bojan AS, Voina CM, Popa S, Visan S, et al. MECOM, HBS1L-MYB, THRB-RARB, JAK2, and TERT polymorphisms defining the genetic predisposition to myeloproliferative neoplasms: a study on 939 patients. Am J Hematol. 2018;93:100–6.CrossRefGoogle Scholar
  29. 29.
    Guglielmelli P, Biamonte F, Spolverini A, Pieri L, Isgro A, Antonioli E, et al. Frequency and clinical correlates of JAK2 46/1 (GGCC) haplotype in primary myelofibrosis. Leukemia. 2010;24:1533–7.CrossRefGoogle Scholar
  30. 30.
    Pardanani A, Lasho TL, Finke CM, Gangat N, Wolanskyj AP, Hanson CA, et al. The JAK2 46/1 haplotype confers susceptibility to essential thrombocythemia regardless of JAK2V617F mutational status-clinical correlates in a study of 226 consecutive patients. Leukemia. 2010;24:110–4.CrossRefGoogle Scholar
  31. 31.
    Waterhouse M, Follo M, Pfeifer D, von Bubnoff N, Duyster J, Bertz H, et al. Sensitive and accurate quantification of JAK2 V617F mutation in chronic myeloproliferative neoplasms by droplet digital PCR. Ann Hematol. 2016;95:739–44.CrossRefGoogle Scholar
  32. 32.
    Tefferi A, Lasho TL, Huang J, Finke C, Mesa RA, Li CY, et al. Low JAK2V617F allele burden in primary myelofibrosis, compared to either a higher allele burden or unmutated status, is associated with inferior overall and leukemia-free survival. Leukemia. 2008;22:756–61.CrossRefGoogle Scholar
  33. 33.
    Tefferi A, Lasho TL, Mudireddy M, Finke CM, Hanson CA, Ketterling RP, et al. The germline JAK2 GGCC (46/1) haplotype and survival among 414 molecularly-annotated patients with primary myelofibrosis. Am J Hematol. 2019;94:299–305.CrossRefGoogle Scholar
  34. 34.
    Krahling T, Balassa K, Kiss KP, Bors A, Batai A, Halm G, et al. Co-occurrence of myeloproliferative neoplasms and solid tumors is attributed to a synergism between cytoreductive therapy and the common TERT polymorphism rs2736100. Cancer Epidemiol Biomarkers Prev. 2016;25:98–104.CrossRefGoogle Scholar

Copyright information

© Japanese Society of Hematology 2019

Authors and Affiliations

  • Masafumi Matsuguma
    • 1
  • Toshiaki Yujiri
    • 2
    Email author
  • Kaoru Yamamoto
    • 1
  • Yasuko Kajimura
    • 1
  • Yoshihiro Tokunaga
    • 1
  • Mayumi Tanaka
    • 1
  • Yoshinori Tanaka
    • 1
  • Yukinori Nakamura
    • 1
  • Yukio Tanizawa
    • 1
  1. 1.Division of Endocrinology, Metabolism, Hematological Sciences and TherapeuticsYamaguchi University Graduate School of MedicineUbeJapan
  2. 2.Division of Clinical Laboratory SciencesYamaguchi University Graduate School of MedicineUbeJapan

Personalised recommendations