Mutational Landscape of Patients Referred for Elevated Hemoglobin Level.

Since the identification of and exon 12 mutations as driver mutations in polycythemia vera (PV) in 2005, molecular testing of these mutations for patients with erythrocytosis has become a routine clinical practice. However, the incidence of myeloid mutations other than the common mutation in unselected patients referred for elevated hemoglobin is not well studied. This study aimed to characterize the mutational landscape in a real-world population of patients referred for erythrocytosis using a targeted next-generation sequencing (NGS)-based assay. A total of 529 patients (hemoglobin levels >160 g/L in females or >165 g/L in males) were assessed between January 2018 and May 2021 for genetic variants using the Oncomine Myeloid Research Assay (ThermoFisher Scientific, Waltham, MA, USA) targeting 40 key genes with diagnostic and prognostic implications in hematological conditions (17 full genes and 23 genes with clinically relevant "hotspot" regions) and a panel of 29 fusion driver genes (>600 fusion partners).   mutations were detected in 10.9% (58/529) of patients, with 57 patients positive for , while one patient had a exon 12 mutation. Additional mutations were detected in 34.5% (20/58) of -positive patients: (11; 19%), (2;3.4%), (2; 3.4%), (2; 3.4%), (1; 1.7%), (1; 1.7%), and (1; 1.7%). Diagnosis of PV was suspected in 2 -negative patients based on the 2016 World Health Organization (WHO) diagnostic criteria. Notably, one patient carried mutations in the and genes, and the other patient carried mutations in the and genes. Three -negative patients with elevated hemoglobin who tested positive for fusion were diagnosed with chronic myeloid leukemia (CML) and excluded from further analysis. The remaining 466 -negative patients were diagnosed with secondary erythrocytosis and mutations were found in 6% (28/466) of these cases. Mutations other than mutations were frequently identified in patients referred for erythrocytosis, with mutations in the and genes being detected in 34.5% of -positive PV patients. The presence of additional mutations, such as in this population has implications for prognosis. Both the incidence and mutation type identified in patients with secondary erythrocytosis likely reflects incidental, age-associated clonal hematopoiesis of indeterminate potential (CHIP).