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Updated: Jul 24, 2025
Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
Case report: Application of targeted NGS for the detection of non-canonical driver variants in MPN
Jin Zhang1,2, Kefeng Shen1, Min Xiao1
1Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Abstract:
Background: JAK2, CALR, and MPL gene mutations are recognized as driver mutations of myeloproliferative neoplasms (MPNs). MPNs without these mutations are called triple-negative (TN) MPNs. Recently, novel mutation loci were continuously discovered using next-generation sequencing (NGS), along with continued discussion and modification of the traditional TN MPN. Case presentation: Novel pathogenic mutations were discovered by targeted NGS in 4 patients who were diagnosed as JAK2 unmutated polycythaemia vera (PV) or TN MPN. Cases 1, 2, and 3 were of patients with PV, essential thrombocythemia (ET), and primary myelofibrosis (PMF); NGS detected JAK2 p.H538_K539delinsQL (uncommon), CALR p.E380Rfs*51 (novel), and MPL p.W515_Q516del (novel) mutations. Case 4 involved a patient with PMF; JAK2, CALR, or MPL mutations were not detected by qPCR or NGS, but a novel mutation SH2B3 p.S337Ffs*3, which is associated with the JAK/STAT signal transduction pathway, was found by NGS. Conclusion: NGS, a more multidimensional and comprehensive gene mutation detection, is required for patients suspected of having MPN to detect non-canonical driver variants and avoid the misdiagnosis of TN MPN. SH2B3 p.S337Ffs*3 can drive MPN occurrence, and SH2B3 mutation may also be a driver mutation of MPN.
Insights
Next-generation sequencing (NGS) identifies novel mutations in myeloproliferative neoplasms (MPNs), including SH2B3, crucial for diagnosing triple-negative MPNs and understanding disease drivers.
Area of Science:
- Hematology
- Genetics
- Molecular Biology
Background:
- Myeloproliferative neoplasms (MPNs) are often driven by mutations in JAK2, CALR, or MPL genes.
- MPNs lacking these mutations are classified as triple-negative (TN) MPNs.
- Next-generation sequencing (NGS) is revealing new mutation loci, prompting reevaluation of TN MPN classification.
Observation:
- Targeted NGS identified novel pathogenic mutations in four patients initially diagnosed with JAK2-unmutated polycythemia vera (PV) or TN MPN.
- Three patients with PV, essential thrombocythemia (ET), and primary myelofibrosis (PMF) had uncommon or novel mutations in JAK2, CALR, and MPL.
- A fourth PMF patient, negative for JAK2, CALR, or MPL mutations by qPCR and NGS, harbored a novel SH2B3 mutation linked to the JAK/STAT pathway.
Findings:
- NGS detected JAK2 p.H538_K539delinsQL, novel CALR p.E380Rfs*51, and novel MPL p.W515_Q516del mutations.
- A novel SH2B3 p.S337Ffs*3 mutation was identified in a triple-negative MPN case.
- The SH2B3 mutation is associated with the JAK/STAT signal transduction pathway.
Implications:
- NGS provides a more comprehensive approach for detecting non-canonical driver variants in MPN diagnosis.
- Accurate identification of mutations like SH2B3 is essential to avoid misclassifying MPNs as triple-negative.
- SH2B3 mutations may represent a novel class of driver mutations contributing to MPN development.
