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Gastric mixed adenoneuroendocrine carcinoma (MANEC) is a clinically aggressive and heterogeneous tumor composed of adenocarcinoma (ACA) and neuroendocrine carcinoma (NEC). The genomic properties and evolutionary clonal origins of MANEC remain unclear. We conduct whole-exome and multiregional sequencing on 101 samples from 33 patients to elucidate their evolutionary paths. We identify four significantly mutated genes, TP53 , RB1 , APC , and CTNNB1. MANEC resembles chromosomal instability stomach adenocarcinoma in that whole-genome doubling in MANEC is predominant and occurs earlier than most copy-number losses. All tumors are of monoclonal origin, and NEC components show more aggressive genomic properties than their ACA counterparts. The phylogenetic trees show two tumor divergence patterns, including sequential and parallel divergence. Furthermore, ACA-to-NEC rather than NEC-to-ACA transition is confirmed by immunohistochemistry on 6 biomarkers in ACA- and NEC-dominant regions. These results provide insights into the clonal origin and tumor differentiation of MANEC. [Display omitted] • Retrospectively collected MANEC specimens using laser-captured microdissection • Whole-genome doubling is a predominant genomic feature of MANEC • All tumors analyzed are of monoclonal origin • The two tumor components are under sequential or parallel divergence process Qiu et al. explore genomic characteristics and tumor clonal origin of gastric mixed adenoneuroendocrine carcinoma (MANEC) and find the predominance of whole-genome doubling in MANEC. All tumors are of monoclonal origin, and they differentiate in a sequential or parallel divergence manner. The ACA-to-NEC transition is further confirmed by immunohistochemistry. [ABSTRACT FROM AUTHOR]