MECOM copy number alterations identify a new group of myeloid neoplasms with a poor prognosis

Abstract

Abstract Objective Myeloid neoplasms (MNs) harboring inv(3)(q21q26)/t(3;3)(q21;q26) or MECOM gene rearrangements as identified by fluorescence in situ hybridization (FISH) are known to carry a poor prognosis. The objective of this study is to assess prognostic impact of MNs with copy number alterations (CNA) in MECOM as compared to MNs with inv(3)/t(3;3) or MECOM rearrangements. We present those initial comparative results and secondarily assess whether genetic mutations that confer a worse clinical outcome are also associated with MNs with MECOM CNA. Methods A retrospective review of electronic pathology records was performed at Beth Israel Deaconess Medical Center. All MNs from 2016 – current with MECOM FISH (Abbott Molecular, Abbott Park, IL) confirmed analyses were extracted. Other additional items extracted included karyotype and next-generation sequencing (NGS) results of a 65 gene myeloid panel (SmartGenomics Myeloid Profile, PathGroup, Nashville, TN). Kaplan-Meier and ANOVA were performed using GraphPad Prism (San Diego, CA). Results A total of 307 cases were identified in which MECOM FISH was performed. Exclusion of cases lacking inv(3)/t(3;3), MECOM rearrangement, or MECOM CNA provided an initial study cohort of 20 cases. 5 cases had MECOM rearrangement with inv(3)/t(3;3), 7 had MECOM rearrangement without inv(3)/t(3;3), and 8 had MECOM CNA. 13 of 20 cases had a complex karyotype, 13 of 20 cases had a monosomal karyotype, 10 of 20 cases had both a complex and monosomal karyotype. Of the 20 cases in which MECOM FISH demonstrated inv(3)/t(3;3), MECOM rearrangement, or CNA, NGS was performed on 16 cases. Genes known to be associated with a significant negative overall survival (OS) include ASXL1, EZH2, IDH2, KRAS, NRAS, RAD21, RUNX1, SRSF2, STAG2, TP53 with single and multiple mutations found in 9 of 20 cases. Kaplan-Meier analysis revealed no significant difference in OS among the three MECOM aberration groupings (Log-rank test; p=0.77). Single factor ANOVA analysis revealed enrichment for high risk gene mutations in MECOM CNA (p=0.04) and TP53 mutations (p=0.04) when compared to MNs with MECOM rearrangements. Summary Our analysis of MNs with MECOM aberrations by FISH reveal that MECOM with CNA display similarly poor overall survival as MNs with inv(3)/t(3;3) and MECOM rearrangements. Additionally, the MECOM CNA group was enriched for high risk gene mutations and TP53 as compared to inv(3)/t(3;3) and MECOM rearrangement groups. Overall, the initial results of this study reveal a new group of MNs harboring MECOM CNA that confer a poor prognosis and high risk mutational profile.