New Target Genes in Endometrial Tumors Show a Role for the Estrogen-Receptor Pathway in Microsatellite-Unstable Cancers

Ana Monteira Ferreira, Iina Tuominen, Sonia Sousa, Frans Gerbens, 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, Jerzy Stachura, Ate G. van der Zee, Harm Hollema, Rolf H. Sijmons, Lauri A. Aaltonen, Raquel SerucaRobert M. W. Hofstra, Helga Westers*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

8 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1514-1523
Number of pages10
JournalHuman Mutation
Volume35
Issue number12
DOIs
Publication statusPublished - Dec-2014

Keywords

  • endometrial cancer
  • colorectal cancer
  • gastric cancer
  • Lynch syndrome
  • mismatch repair
  • microsatellite instability
  • NRIP1
  • target genes
  • COLORECTAL-CANCER
  • SOMATIC MUTATIONS
  • MUTATOR PHENOTYPE
  • COLON-CANCER
  • FRAMESHIFT MUTATIONS
  • GASTRIC CARCINOMAS
  • INSTABILITY
  • EXPRESSION
  • HORMONES
  • PROTEIN

Cite this