Targeted deep sequencing in polycythemia vera and essential thrombocythemia

Area of Science:

• Hematology
• Oncology
• Genetics

Background:

• Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms.
• These conditions are often characterized by mutations in JAK2, CALR, and MPL genes.
• The prognostic significance of other genetic variants in PV and ET requires further investigation.

Purpose of the Study:

• To identify and evaluate the prognostic relevance of DNA sequence variants/mutations other than JAK2, CALR, and MPL in patients with PV and ET.
• To determine if these additional mutations impact overall survival, leukemia-free survival, and myelofibrosis-free survival.
• To assess the utility of targeted deep sequencing for genetic risk stratification in PV and ET.

Main Methods:

• Next-generation sequencing of a 27-gene panel was performed on bone marrow or whole blood DNA from patients with PV and ET.
• Age-adjusted multivariable analysis was used to identify "adverse variants/mutations" impacting survival.
• The findings were validated in independent patient cohorts from Mayo Clinic and Italy.

Main Results:

• Over half of PV and ET patients harbored mutations other than JAK2/CALR/MPL, with TET2 and ASXL1 being most frequent.
• "Adverse variants/mutations" (e.g., ASXL1, SRSF2, IDH2 in PV; SH2B3, SF3B1, U2AF1, TP53, IDH2, EZH2 in ET) were identified in 15% of each cohort.
• These adverse mutations were associated with significantly inferior survival (PV: 7.7 vs 16.9 years; ET: 9 vs 22 years) and predicted leukemic or fibrotic progression, independent of conventional models.

Conclusions:

• Targeted deep sequencing reveals additional genetic variants in PV and ET that carry prognostic significance.
• Identification of these adverse mutations allows for genetic risk stratification independent of current clinical models.
• This approach can improve prognostic accuracy and guide treatment strategies for patients with PV and ET.