Ann Lab Med.  2015 Mar;35(2):233-237. 10.3343/alm.2015.35.2.233.

Incidence, Clinical Features, and Prognostic Impact of CALR Exon 9 Mutations in Essential Thrombocythemia and Primary Myelofibrosis: An Experience of a Single Tertiary Hospital in Korea

• Park SH
• Kim SY
• Lee SM
• Yi J
• Kim IS
• Kim HH
• Chang CL
• Lee EY
• Song MK
• Shin HJ
• Chung JS

• KMID: 2363184
• DOI: http://doi.org/10.3343/alm.2015.35.2.233

Abstract

We evaluated the incidence, clinical characteristics, and prognostic impact of calreticulin (CALR) mutations in essential thrombocythemia (ET) and primary myelofibrosis (PMF) patients. In all, 48 ET and 14 PMF patients were enrolled, and the presence of CALR mutations was analyzed by direct sequencing. Patients were classified into three subgroups according to Janus kinase 2 (JAK2) V617F and CALR mutation status, and their clinical features and prognosis were compared. CALR mutations were detected in 15 (24.2%) patients, and the incidence increased to 50.0% in 30 JAK2 V617F mutation-negative cases. These included 11 patients with three known mutations (c.1092_1143del [seven cases], c.1154_1155insTTGTC [three cases], and c.1102_1135del [one case]) and 4 patients with novel mutations. ET patients carrying CALR mutation were younger, had lower white blood cell counts, and experienced less thrombosis during follow-up than those carrying JAK2 V617F mutation, while both patient groups showed similar clinical features and prognosis. In ET patients without JAK2 V617F mutation, CALR mutation did not significantly affect clinical manifestation and prognosis. In conclusion, CALR mutation analysis could be a useful diagnostic tool for ET and PMF in 50% of the cases without JAK2 V617F mutations. The prognostic impact of CALR mutations needs further investigation.

Keyword

CALR; Clinical feature; Essential thrombocythemia; Incidence; Mutation; Primary myelofibrosis; Prognosis

MeSH Terms

Adult
Aged
Calreticulin/*genetics
DNA Mutational Analysis
Exons
Female
Genotype
Humans
INDEL Mutation
Janus Kinase 2/genetics
Male
Middle Aged
Primary Myelofibrosis/diagnosis/epidemiology/*genetics
Prognosis
Republic of Korea
Tertiary Care Centers
Thrombocythemia, Essential/diagnosis/epidemiology/*genetics
Young Adult
Calreticulin
Janus Kinase 2

Reference

1. Swerdlow SH, Campo E, editors. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. Lyon: IARC;2008.

2. Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med. 2007; 356:459–468. PMID: 17267906.

3. Butcher CM, Hahn U, To LB, Gecz J, Wilkins EJ, Scott HS, et al. Two novel JAK2 exon 12 mutations in JAK2V617F-negative polycythaemia vera patients. Leukemia. 2008; 22:870–873. PMID: 17914411.

4. Campbell PJ, Scott LM, Buck G, Wheatley K, East CL, Marsden JT, et al. Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study. Lancet. 2005; 366:1945–1953. PMID: 16325696.

5. Campbell PJ, Griesshammer M, Döhner K, Döhner H, Kusec R, Hasselbalch HC, et al. V617F mutation in JAK2 is associated with poorer survival in idiopathic myelofibrosis. Blood. 2006; 107:2098–2100. PMID: 16293597.

6. Bench AJ, White HE, Foroni L, Godfrey AL, Gerrard G, Akiki S, et al. Molecular diagnosis of the myeloproliferative neoplasms: UK guidelines for the detection of JAK2 V617F and other relevant mutations. Br J Haematol. 2013; 160:25–34. PMID: 23057517.

7. Passamonti F, Elena C, Schnittger S, Skoda RC, Green AR, Girodon F, et al. Molecular and clinical features of the myeloproliferative neoplasm associated with JAK2 exon 12 mutations. Blood. 2011; 117:2813–2816. PMID: 21224469.

8. Rumi E, Pietra D, Guglielmelli P, Bordoni R, Casetti I, Milanesi C, et al. Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative. Acquired copy-neutral loss of heterozygosity of chromosome 1p as a molecular event associated with marrow fibrosis in MPL-mutated myeloproliferative neoplasms. Blood. 2013; 121:4388–4395. PMID: 23575445.

9. Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013; 369:2379–2390. PMID: 24325356.

10. Rumi E, Pietra D, Ferretti V, Klampfl T, Harutyunyan AS, Milosevic JD, et al. JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood. 2014; 123:1544–1551. PMID: 24366362.

11. Tefferi A, Lasho TL, Finke CM, Knudson RA, Ketterling R, Hanson CH, et al. CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia. 2014; 28:1472–1477. PMID: 24402162.

12. Tefferi A, Guglielmelli P, Lasho TL, Rotunno G, Finke C, Mannarelli C, et al. CALR and ASXL1 mutations-based molecular prognostication in primary myelofibrosis: an international study of 570 patients. Leukemia. 2014; 28:1494–1500. PMID: 24496303.

13. Rumi E, Harutyunyan AS, Pietra D, Milosevic JD, Casetti IC, Bellini M, et al. CALR exon 9 mutations are somatically acquired events in familial cases of essential thrombocythemia or primary myelofibrosis. Blood. 2014; 123:2416–2419. PMID: 24553179.

14. Gangat N, Wassie EA, Lasho TL, Finke C, Ketterling RP, Hanson CA, et al. Mutations and thrombosis in essential thrombocythemia: prognostic interaction with age and thrombosis history. Eur J Haematol. 2014; 6. 3. doi: 10.1111/ejh.12389 [Epub ahead of print].

15. 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; 369:2391–2405. PMID: 24325359.

16. Tefferi A, Thiele J, Vannucchi AM, Barbui T. An overview on CALR and CSF3R mutations and a proposal for revision of WHO diagnostic criteria for myeloproliferative neoplasms. Leukemia. 2014; 28:1407–1413. PMID: 24441292.

17. Li B, Xu J, Wang J, Gale RP, Xu Z, Cui Y, et al. Calreticulin mutations in Chinese with primary myelofibrosis. Haematologica. 2014; 99:1697–1700. PMID: 24997152.

18. Shen H, Chao H, Ding Z, Feng Y, Cen J, Pan J, et al. CALR and ASXL1 mutation analysis in 190 patients with essential thrombocythemia. Leuk Lymphoma. 2014; 8. 13. 1–3. [Epub ahead of print]. PMID: 25005031.

19. Chen CC, Gau JP, Chou HJ, You JY, Huang CE, Chen YY, et al. Frequencies, clinical characteristics, and outcome of somatic CALR mutations in JAK2-unmutated essential thrombocythemia. Ann Hematol. 2014; 7. 13. [Epub ahead of print].

20. Passamonti F, Cervantes F, Vannucchi AM, Morra E, Rumi E, Pereira A, et al. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood. 2010; 115:1703–1708. PMID: 20008785.