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This study represents the most comprehensive next-generation sequencing analysis of EMM tumors (<jats:italic>N<\/jats:italic>\u2009=\u200914) to date, uncovering key molecular features and describing the tumor microenvironment. We observed the co-occurrence of 1q21 gain\/amplification and MAPK pathway mutations in 79% of EMM samples, suggesting that these are crucial mutational events in EMM development. We also demonstrated that patients with mutated <jats:italic>KRAS<\/jats:italic> and 1q21 gain\/amplification at the time of diagnosis have a significantly higher risk of EMM development (HR\u2009=\u20092.4, <jats:italic>p<\/jats:italic>\u2009=\u20090.011) using data from a large CoMMpass dataset. We identified downregulation of CXCR4 and enhanced cell proliferation, along with reduced expression of therapeutic targets (CD38, SLAMF7, GPRC5D, FCRH5), potentially explaining diminished efficacy of immunotherapy. 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