Abstract
6595Background: Polycythemia vera (PV) is a myeloproliferative neoplasm associated with blood thickening and increased risk of life-threatening blood clots and bleeding. PV is rare and affects roughly 50 per 100,000 people in the US. PV is most commonly associated with a somatic mutation in the JAK2 gene and the mean age of diagnosis is 60. The JAK2 gene is critical for cell signaling, and cell maturation. Treatments for PV include immunotherapy, radiation and chemotherapy but this can only slow growth, underscoring the need to define molecular drivers for targeted therapies. Using the AACR GENIE database, this study characterizes the mutational landscape of PV to identify genetic markers and therapeutic targets. Methods: The American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database was accessed from cBioPortal (v18.1-public) on November 20, 2025 to identify all patients with PV. The most common gene mutations, demographic correlations, and mutual exclusivities were analyzed using a two-sided T-test and non-parametric tests, with Benjamini-Hochberg false discovery rate (FDR) correction. Results: The cohort comprised 491 PV samples from 341 patients. The patient population consisted of adults(19-88 years old, n=341,100%). Males (n=171, 50.1%) were represented as equally as females (n=163, 47.8%), with some unknown cases (n=7, 2.1%). By race, the cohort consisted primarily of White (n=236, 69.2%), Black (n=13, 3.8%), and Asian (n=17, 5.0) patients, with the remaining patients (n=75, 22.0%) categorized as having an unspecified or other race. Of the samples derived from 90 tumors which were classified as primary (n=80, 16.3%) or metastatic (n=10, 2.0%), the most frequent somatic mutations were observed in JAK2 (87.17%, n=428), TERT2 (18.53%, n=91), DNMT3A (14.87%, n=73), ASXL1 (5.50%, n=27), and TP53 (3.05%, n=15). When stratified by sex, sex-associated mutational variability was observed. Specifically, mutations in NF1 (n=13, p < 0.001) were detected only in females. DNMT3A mutations occurred at a higher frequency in females compared to males (n=48 v. n=23; p < 0.001). AXSL1 mutations occur at a higher frequency in males compared to females (n=23 v. n=4; p < 0.001 ). Conclusions: To the best of our knowledge, this is the first GENIE database analysis of polycythemia vera, thus addressing a significant research gap regarding its genomic landscape. The predominance of JAK2 and TERT2 align with earlier descriptions in prior genetic profiling studies. Sex specific mutations underscore the importance of demographic-specific molecular features. Collectively, these findings suggest that JAK2 and TERT2 could serve as key genomic targets for the development of novel precision therapeutics. Further research is needed to validate these genomic associations and advance precision medicine approaches for patients with PV.