title: Identification of CUX1 as the recurrent chromosomal band 7q22 target gene in human uterine leiomyoma.
abstract: Uterine leiomyomas are benign solid tumors of mesenchymal origin which occur with an estimated incidence of up to 77% of all women of reproductive age. The majority of these tumors remains symptomless, but in about a quarter of cases they cause leiomyoma-associated symptoms including chronic pelvic pain, menorrhagia-induced anemia, and impaired fertility. As a consequence, they are the most common indication for pre-menopausal hysterectomy in the USA and Japan and annually translate into a multibillion dollar healthcare problem. Approximately 40% of these neoplasms present with recurring structural cytogenetic anomalies, including del(7)(q22), t(12;14)(q15;q24), t(1;2)(p36;p24), and anomalies affecting 6p21 and/or 10q22. Using positional cloning strategies, we and others previously identified HMGA1, HMGA2, RAD51L1, MORF, and, more recently, NCOA1 as primary target (fusion) genes associated with tumor initiation in four of these distinct cytogenetic subgroups. Despite the fact that the del(7)(q22) subgroup is the largest among leiomyomas, and was first described more than twenty years ago, the 7q22 leiomyoma target gene still awaits unequivocal identification. We here describe a positional cloning effort from two independent uterine leiomyomas, containing respectively a pericentric and a paracentric chromosomal inversion, both affecting band 7q22. We found that both chromosomal inversions target the cut-like homeobox 1 (CUX1) gene on chromosomal band 7q22.1 in a way which is functionally equivalent to the more frequently observed del(7q) cases, and which is compatible with a mono-allelic knock-out scenario, similar as was previously described for the cytogenetic subgroup showing chromosome 14q involvement.
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre and Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands. Eric.Schoenmakers@Pfizer.com
authors.forename: Eric F P M
authors.initials: EF
authors.lastname: Schoenmakers
authors.forename: Jens
authors.initials: J
authors.lastname: Bunt
authors.forename: Lianne
authors.initials: L
authors.lastname: Hermers
authors.forename: Marga
authors.initials: M
authors.lastname: Schepens
authors.forename: Gerard
authors.initials: G
authors.lastname: Merkx
authors.forename: Bert
authors.initials: B
authors.lastname: Janssen
authors.forename: Monique
authors.initials: M
authors.lastname: Kersten
authors.forename: Erik
authors.initials: E
authors.lastname: Huys
authors.forename: Patrick
authors.initials: P
authors.lastname: Pauwels
authors.forename: Maria
authors.initials: M
authors.lastname: Debiec-Rychter
authors.forename: Ad Geurts
authors.initials: AG
authors.lastname: van Kessel
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics*; D002897:Chromosomes, Human, Pair 7; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007889:Leiomyoma / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D014157:Transcription Factors; D014594:Uterine Neoplasms / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C080632:CUX1 protein, human; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors