Investigating gender-based differences in the molecular profile of myeloid neoplasms: Insights from an institutional genomic database.

Abstract

e18598 Background: Myeloid neoplasms exhibit significant gender-based differences in mutations and outcomes. Men have been shown to harbor more somatic mutations, particularly in pathways like chromatin modification and DNA repair, contributing to poorer clinical outcomes. To further investigate these reported differences in a mutation specific manner, we analyzed gender-specific mutational profiles using our institutional genomic database. Methods: We conducted a retrospective analysis using our hematologic next generation sequencing dataset (cBioPortal). The study evaluated the frequency and distribution of driver mutations, tumor suppressor genes, and oncogenes across the two genders. Mutations in ASXL1, RUNX1, TP53, IDH1/IDH2, FLT3, NPM1, CEBPA were classified as high-risk due to their association with shorter time to leukemic progression, poorer prognosis, and variable response to treatment. Other high-risk mutations considered were U2AF1, SRSF2, NRAS, KRAS, EZH2 , and MLL, as they can also play significant roles in myeloid neoplasm pathogenesis. The data was analyzed using descriptive statistics and chi-square test, with significance defined by p-value <0.05 and a minimum false discovery rate set at a q-value <0.05. Results: The cohort included 1940 women and 2107 men. Certain somatic mutations including ASXL1, MFSD11, KMT2A, RUNX1, U2AF1 and BRAF were significantly higher in males compared to females. The ASXL1 gene was mutated in 16.88% males (n=350) and 12.08% females (n=235), with a p-value <0.001 and a q-value <0.001. The MFSD11 gene showed a higher prevalence in males (8.73%, n=181) compared to females (3.86%, n=75), with a p-value <0.001 and q-value <0.001. KMT2A mutations affected 8.63% males (n=179) and 6.07% females (n=118), with a p-value <0.001 and q-value <0.005. RUNX1 was found in 6.46% males (n=134) and 3.60% females (n=70), with a p-value <0.001 and q-value <0.001. U2AF1 mutation exhibited a significant sex-based difference, affecting 5.31% males (n=110) compared to 1.95% females (n=38), with a p-value and q-value both <0.001. Lastly, BRAF mutations are present in 0.96% males (n=20) and 0.15% females (n=3), with a p-value <0.001 and q-value <0.001. Conclusions: Our findings reveal that men with myeloid neoplasms, compared to women, are more likely to harbor somatic mutations in genes ASXL1, MFSD11, KMT2A, RUNX1, U2AF1 and BRAF . Notably, ASXL1, RUNX1 and U2AF1 are high-risk mutations associated with aggressive disease, poor outcomes, and reduced survival rates. Further investigation in larger cohorts is needed to uncover underlying molecular mechanisms, which could inform prognostic strategies and optimize treatment approaches, including early intervention with intensive therapies, targeted therapies, and timing of stem cell transplantation.