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Microsatellite instability (MSI) in tumors results in an accumulation of mutations in (target) genes. Previous studies suggest that the profile of target genes differs according to tumor type. This paper describes the first genome-wide search for target genes for mismatch repair-deficient endometrial cancers. Genes expressed in normal endometrium containing coding repeats were analyzed for mutations in tumors. We identified 44 possible genes of which seven are highly mutated (>15%). Some candidates were also found mutated in colorectal and gastric tumors. The most frequently mutated gene,NRIP1encoding nuclear receptor-interacting protein 1, was silenced in an endometrial tumor cell line and expression microarray experiments were performed. Silencing ofNRIP1was associated with differences in the expression of several genes in the estrogen-receptor network. Furthermore, an enrichment of genes related to cell cycle (regulation) and replication was observed. We present a new profile of target genes, some of them tissue specific, whereas others seem to play a more general role in MSI tumors. The high-mutation frequency combined with the expression data suggest, for the first time, an involvement ofNRIP1in endometrial cancer development.A genome-wide search for target genes in endometrial tumors with microsatellite instability.Seven highy mutated genes were found in endometrial cancer; some of them were also found mutated in colorectal and gastric tumors.The most mutated gene, NRIP1, was silenced in an endometrial cell line, which revealed an association with differences in the expression of several genes in the estrogen-receptor network.