Mutational Landscape of Patients Referred for Elevated Hemoglobin Level

Area of Science:

• Hematology
• Oncology
• Genetics

Background:

• JAK2 V617F and exon 12 mutations are established drivers in polycythemia vera (PV).
• The spectrum of other myeloid mutations in patients with unexplained erythrocytosis is not well characterized.
• Routine molecular testing is crucial for diagnosing and managing erythrocytosis.

Purpose of the Study:

• To investigate the mutational landscape in a real-world cohort of patients referred for erythrocytosis.
• To identify myeloid mutations beyond JAK2 V617F using next-generation sequencing (NGS).
• To assess the clinical implications of identified mutations in erythrocytosis patients.

Main Methods:

• A targeted NGS assay (Oncomine Myeloid Research Assay) was used.
• 529 patients with elevated hemoglobin levels were analyzed between January 2018 and May 2021.
• The assay targeted 40 key genes and 29 fusion driver genes.

Main Results:

• JAK2 mutations were found in 10.9% of patients (58/529), predominantly JAK2 V617F.
• Additional mutations (TET2, DNMT3A, ASXL1, SRSF2) were detected in 34.5% of JAK2-positive patients.
• In JAK2-negative patients with secondary erythrocytosis, mutations were found in 6% (28/466), potentially reflecting clonal hematopoiesis of indeterminate potential (CHIP).

Conclusions:

• Mutations other than JAK2 are common in patients with erythrocytosis.
• The presence of mutations like ASXL1 in JAK2-positive PV patients has prognostic significance.
• Findings in JAK2-negative patients suggest age-associated CHIP contributes to elevated hemoglobin.