title: New target genes in endometrial tumors show a role for the estrogen-receptor pathway in microsatellite-unstable cancers.
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.
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Pathomorphology, Medical College, Jagiellonian University, Krakow, Poland; Institute of Molecular Pathology and Immunology and Medical Faculty, University of Porto, Porto, Portugal.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Ferreira
authors.forename: Iina
authors.initials: I
authors.lastname: Tuominen
authors.forename: Sónia
authors.initials: S
authors.lastname: Sousa
authors.forename: Frans
authors.initials: F
authors.lastname: Gerbens
authors.forename: Krista
authors.initials: K
authors.lastname: van Dijk-Bos
authors.forename: Jan
authors.initials: J
authors.lastname: Osinga
authors.forename: Krista A
authors.initials: KA
authors.lastname: Kooi
authors.forename: Bahram
authors.initials: B
authors.lastname: Sanjabi
authors.forename: Chris
authors.initials: C
authors.lastname: Esendam
authors.forename: Carla
authors.initials: C
authors.lastname: Oliveira
authors.forename: Peter
authors.initials: P
authors.lastname: Terpstra
authors.forename: Menno
authors.initials: M
authors.lastname: Hardonk
authors.forename: Tineke
authors.initials: T
authors.lastname: van der Sluis
authors.forename: Monika
authors.initials: M
authors.lastname: Zazula
authors.forename: Jerzy
authors.initials: J
authors.lastname: Stachura
authors.forename: Ate G
authors.initials: AG
authors.lastname: van der Zee
authors.forename: Harry
authors.initials: H
authors.lastname: Hollema
authors.forename: Rolf H
authors.initials: RH
authors.lastname: Sijmons
authors.forename: Lauri A
authors.initials: LA
authors.lastname: Aaltonen
authors.forename: Raquel
authors.initials: R
authors.lastname: Seruca
authors.forename: Robert M W
authors.initials: RM
authors.lastname: Hofstra
authors.forename: Helga
authors.initials: H
authors.lastname: Westers
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics*; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D000078723:Nuclear Receptor Interacting Protein 1; D060888:Real-Time Polymerase Chain Reaction; D011960:Receptors, Estrogen / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; C000627127:NRIP1 protein, human; D009687:Nuclear Proteins; D000078723:Nuclear Receptor Interacting Protein 1; D011960:Receptors, Estrogen
keywords: Lynch syndrome; NRIP1; colorectal cancer; endometrial cancer; gastric cancer; microsatellite instability; mismatch repair; target genes