Atypical variants of driver genes in Ph-negative MPN

A mutation in driver genes, such as JAK2, MPL, and CALR, is one of the main criteria for diagnosing Philadelphia (Ph)-negative myeloproliferative neoplasms (MPN). The co-existence of mutations in atypical variants of driver genes may also impact the JAK-STAT pathway and thereby MPN disease severity.

Here, we summarize a study by Wang et al.¹ published in Cancer Medicine investigating atypical variants of driver mutations using next-generation sequencing (NGS).

Study design¹

• Patients from China with an initial diagnosis of Ph-negative MPN with JAK2, MPL, or CALR mutations were studied from August 2017 to October 2022.
• Patients were divided into groups by mutation status (with or without atypical driver mutations) and assessed according to MPN subtype diagnosis: essential thrombocythemia (ET), polycythemia vera (PV), or overt primary myelofibrosis (overt-PMF).

Key findings¹

• Overall, 359 patient cases were included.
• Of these, 55 patients (15%) expressed atypical variants of driver genes (Figure 1).

ET, essential thrombocytopenia, MPN, myeloproliferative neoplasms; PMF, primary myelofibrosis, PV, polycythemia vera.
*Adapted from Wang et al.¹

• Of the 85% of patients without atypical variants of driver genes, incidence of classical driver mutations were:
  • 81% with JAK2;
  • 16% with CALR;
  • 3% with MPL.
• In total, 30 atypical variants of JAK2, MPL, and CALR were reported and 51% were male.
• The median age was 64 years.
  • Patients with ET and atypical variants tended to be older than patients without atypical variants (70 years vs 61 years).
• The incidence of MPL mutations was higher in patients with ET who have atypical variants of driver genes vs without, but similar between other Ph-negative subgroups (Figure 2).

ET, essential thrombocythemia; PMF, primary myelofibrosis; PV, polycythemia vera.
*Adapted from Wang et al.¹

Key learnings

Within a study population of 359 patients with MPN, 15% had atypical variants of JAK2, MPL, or CALR. Overall, 30 different atypical variants of JAK2, MPL, and CALR were identified, and atypical JAK2 variants were more common than atypical variants of MPL and CALR. Future studies should aim to further explore the roles of atypical variant mutations in genetic pathways underlying MPN, and their implications for prognosis and treatment.