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Myeloproliferative Neoplasm Diagnosis: Molecular Evaluation

Test codes: 92473, 92474, 92475, 92476, 92477, 91065, 90665, 36788, 13010

Tests used for diagnostic evaluation of MPNs vary based on the particular hematologic abnormalities observed, as shown below. If the specimen is negative for the BCR/ABL1 translocation, then additional testing, such as the MPN Core Diagnostic Panel or LeukoVantage®, Myeloproliferative Neoplasms (MPN), may be considered.

Click on the table to open (enlarged) in a new window.

The suggestions are based primarily on the 2022 World Health Organization1 and International Consensus Conference2 classifications of myeloid neoplasms and acute leukemia. Genes most closely associated with the various MPNs are shown below.

Genes most closely associated with the various MPNs.

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This panel includes multiplex PCR and next-generation sequencing (NGS) analysis for all the currently well-characterized MPN-associated driver variants in the following genes:

  • JAK2 variants at codon 617 (exon 14) and exon 12
  • CALR frame-shift variants in exon 9
  • MPL variants at codons 505 and 515 (exon 10)

Results are reported for all analytes tested. MPN patients who are found to be pan-negative (~10% of cases) on the MPN Core Diagnostic Panel may be candidates for Quest’s LeukoVantage®, Myeloproliferative Neoplasms (MPN) panel (test code 36788), which offers an expanded panel of gene targets supported by medical literature.

Yes, the following single-analyte test codes are available:

92473:        JAK2 V617F Mutation Analysis

92474:        JAK2 Exon 12 Mutation Analysis

92475:        Calreticulin (CALR) Mutation Analysis

92476:        MPL Mutation Analysis

92477:        CSF3R Mutation Analysis

Peripheral blood and bone marrow aspirates are the acceptable specimen types. Specimens are stable for 7 days, but they should be sent immediately after collection whenever possible. See the online Test Directory for specimen volumes and acceptable collection tubes.

Variants in JAK2, CALR, MPL, and CSF3R are all detected in DNA extracted from leukocytes using next-generation sequencing (NGS). The sensitivity for variant detection is set at 5% variant alleles, which is lower than that of traditional Sanger DNA sequencing. Given the unclear significance of occult or low levels of these variants,6 the 5% sensitivity is appropriate for a diagnostic MPN assay. The percentage of variant reads is reported, so it can be compared with that in subsequent tests. Insertions up to 30 bp and deletions up to 52 bp have been successfully detected by the assays.

The BCR/ABL1 gene rearrangement test is not included in our next-generation sequencing (NGS) offerings because the former is an RNA-based test rather than a DNA-based test. RNA-based technology is better for detecting fusion transcripts such as BCR/ABL1. Additionally, BCR/ABL1 fusion transcript results must be normalized and reported according to the International Scale (IS). This requires copy number of both BCR/ABL1 and ABL1 RNA transcripts. For additional information on the BCR/ABL1 test, including identification of the P190 vs P210 breakpoints, see the following:

If eosinophilia is a prominent feature in a patient with suspected MPN, the following tests should be considered.

  • BCR/ABL1 Gene Rearrangement, Quantitative, PCR (91065)
  • FISH, Myeloproliferative Neoplasms (Eosinophilia) (90665)

The FISH test includes probes for PDGFRA (4q12), PDGFRB (5q33.1), and FGFR1 (8p11-12). PDGFRA, PDGFRB, and FGFR1 rearrangements occur in MPN with eosinophilia (including hypereosinophilic syndrome) and result in activation of tyrosine kinases. 

Other causes of eosinophilia and myeloid proliferation, including coexistent lymphoma, should also be considered.

References

  1. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022;36:1703-1719. doi:10.1038/s41375-022-01613-1
  2. Arber DA, Orazi A, Hasserjian RP, et al. International consensus classification of myeloid neoplasms and acute leukemia: integrating morphologic, clinical, and genomic data. Blood. 2022;140(11):1200-1228. doi:10.1182/blood.2022015850
  3. Vannucchi AM, Barbui T, Cervantes F, et. al. Philadelphia chromosome-negative chronic myeloproliferative neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up. Ann Oncol. 2015;26 (Supplement 5):v85-v99. doi:10.1093/annonc/mdv203
  4. Langabeer SE, Andrikovics H, Asp J, et al. Molecular diagnostics of myeloproliferative neoplasms. Eur J Haematol. 2015;95(4):270-279. doi:10.1111/ejh.12578
  5. Tefferi A, Thiele J, Vannucchi AM, et al. An overview on CALR and CSF3R mutations and a proposal for revision of WHO diagnostic criteria for myeloproliferative neoplasms. Leukemia. 2014;28:1407-1413. doi:10.1038/leu.2014.35
  6. Pardanani A, Lasho TL, Hussein K, et al. JAK2V617F mutation screening as part of the hypercoagulable work-up in the absence of splanchnic venous thrombosis or overt myeloproliferative neoplasm: assessment of value in a series of 664 consecutive patients. Mayo Clin Proc. 2008;83:457-459. doi:10.4065/83.4.457
  7. Lundberg P, Karow A, Nienhold R, et al. Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms. Blood. 2014;123:2220-2228. doi:10.1182/blood-2013-11-537167
  8. Schnittger S, Bacher U, Eder C, et al. Molecular analyses of 15,542 patients with suspected BCR/ABL1-negative myeloproliferative disorders allow to develop a stepwise diagnostic workflow. Haematologica. 2012;97(10):1582-1585. doi:10.3324/haematol.2012.064683
  9. Ortmann CA, Kent DG, Nangalia J, et al. Effect of mutation order on myeloproliferative neoplasms. N Engl J Med. 2015;372(7):601-612. doi:10.1056/NEJMoa1412098
  10. Patel AA, Odenike O. Genomics of MPN Progression. Hematology Am Soc Hematol Educ Program. 2020;2020(1):440-449. doi:10.1182/hematology.2020000129
  11. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365(9464):1054-1061. doi:10.1016/S0140-6736(05)71142-9
  12. Klampfl T, Gisslinger H, Harutyunyan AS et. al. Somatic Mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013; 369(25):2379-2390. doi:10.1056/NEJMoa1311347
  13. Tefferi A and Barbui T. Polycythemia vera and essential thrombocythemia: 2021 update on diagnosis, risk-stratification and management. Am J Hematol. 2020;95(12):1599-1613. doi:10.1002/ajh.26008
  14. Eldeweny S, Ibrahim H, Elsayad G, et al. MPL W515L/K mutations in myeloproliferative neoplasms. Egyptian J Med Hum Genet. 2019;20(31):1-7. doi:10.1186/s43042-019-0039-9

 

This FAQ is provided for informational purposes only and is not intended as medical advice. A physician’s test selection and interpretation, diagnosis, and patient management decisions should be based on the physician’s education, clinical expertise, and assessment of the patient.

Document FAQS.211 Version: 1

Version 1: Effective 09/18//2023 to present

Version 0: Effective 01/28/2019 to 09/18//2023

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