New Target Genes in Endometrial Tumors Show a Role for the Estrogen‐Receptor Pathway in Microsatellite‐Unstable Cancers |
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| Authors: | Sónia Sousa Krista van Dijk‐Bos Jan Osinga Krista A. Kooi Bahram Sanjabi Chris Esendam Carla Oliveira Peter Terpstra Menno Hardonk Tineke van der Sluis Monika Zazula Ate G. van der Zee Harry Hollema Rolf H. Sijmons Lauri A. Aaltonen Raquel Seruca Helga Westers |
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| Affiliation: | 1. Institute of Molecular Pathology and Immunology and Medical Faculty, University of Porto, Porto, Portugal;2. Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands;3. Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands;4. Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands;5. Pathology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands;6. Department of Pathomorphology, Medical College, Jagiellonian University, Krakow, Poland;7. Gynecology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands;8. Department of Medical Genetics, University of Helsinki, Helsinki, Finland |
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| Abstract: | 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, NRIP1 encoding nuclear receptor‐interacting protein 1, was silenced in an endometrial tumor cell line and expression microarray experiments were performed. Silencing of NRIP1 was 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 of NRIP1 in endometrial cancer development. |
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| Keywords: | endometrial cancer colorectal cancer gastric cancer Lynch syndrome mismatch repair microsatellite instability NRIP1 target genes |
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