MECOM amplified endometrial cancer, a novel subset of copy number high tumors associated with poor prognosis

Objective: Copy number high (CNH) endometrial cancer (EC) is an aggressive molecular subgroup characterized by TP53 mutations and relative chemoresistance. CNH EC with cyclin E1 gene (CCNE1) amplification and erythroblastic oncogene B (ERBB2) amplification are associated with poor clinical outcomes. MECOM, a complex locus of MDS1 (myelodysplasia syndrome 1) and EVI1 (ecotropic virus integration site 1), has recently been associated with poor prognosis in ovarian cancer. Our objective was to evaluate clinical outcomes of MECOM, CCNE1 and ERBB2 amplified ECs and to provide a literature review on the role of MECOM in gynecologic cancers. Methods: Copy number variation and molecular subtype classification were extracted from The Cancer Genome Atlas for 529 ECs. Amplification status was determined for MECOM, CCNE1 and ERBB2. Measured clinical outcomes were overall and progression-free survival, covariates included race, stage at diagnosis, and tumor histology. A comprehensive search of peer-reviewed articles was undertaken to summarize evidence on the role of MECOM in gynecologic cancers. Results: Of all ECs profiled, MECOM was the most frequently amplified gene. Notably, 35% of CNH ECs were MECOM amplified. In multivariate analysis, MECOM amplification without co-amplification of CCNE1 or ERBB2 was associated with an increased risk of death and recurrence, HR 2.3 [1.17–4.62], p = 0.0163 and HR 2.07 [1.08–3.98], p = 0.0282, respectively. The literature review identified 19 relevant studies with inconsistent evidence on MECOM's role in carcinogenesis. Conclusions: ECs with MECOM amplification are associated with poor clinical outcomes, even in the absence of CCNE1 or ERBB2 amplification. The current literature is limited, and further studies are warranted to determine the role of MECOM amplification in ECs.