title: Chromatin remodelling and DNA repair genes are frequently mutated in endometrioid endometrial carcinoma.
abstract: In developed countries, endometrial carcinoma is the most common cancer that affects the female genital tract. Endometrial carcinoma is divided into two main histological types, type I or endometrioid and type II or non-endometrioid, each of which have characteristic, although not exclusive, molecular alterations and mutational profiles. Nevertheless, information about the implication and relevance of some of these genes in this disease is lacking. We sought here to identify new recurrently mutated genes in endometrioid cancers that play a role in tumourigenesis and that influence the clinical outcome. We focused on low-grade, non-ultramutated tumours as these tumours have a worse prognosis than the ultramutated POLE-positive endometrioid endometrial carcinomas (EECs). We performed exome-sequencing of 11 EECs with matched normal tissue and subsequently validated 15 candidate genes in 76 samples. For the first time, we show that mutations in chromatin remodelling-related genes (KMT2D, KMT2C, SETD1B and BCOR) and in DNA-repair-related genes (BRCA1, BRCA2, RAD50 and CHD4) are frequent in this subtype of endometrial cancer. The alterations to these genes occurred with frequencies ranging from 35.5% for KMT2D to 10.5% for BRCA1 and BCOR, with some showing a tendency toward co-occurrence (RAD50-KMT2D and RAD50-SETD1B). All these genes harboured specific mutational hotspots. In addition, the mutational status of KMT2C, KMT2D and SETD1B helps to predict the degree of myometrial invasion, a critical prognostic feature. These results highlight the possible implication of these genes in this disease, creating opportunities for new therapeutic approaches.
authors.affiliation: MD Anderson International Foundation, Madrid, Spain.|Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), Madrid, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: García-Sanz
authors.affiliation: Sistemas Genómicos, Valencia, Spain.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Triviño
authors.affiliation: MD Anderson International Foundation, Madrid, Spain.|Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), Madrid, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Mota
authors.affiliation: MD Anderson International Foundation, Madrid, Spain.|Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Pérez López
authors.affiliation: Department of Pathology and Molecular Genetics/Oncologic Pathology Group, Arnau de Vilanova University Hospital, University of Lleida, IRBLleida, Lleida, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Colás
authors.affiliation: Department of Pathology, MD Anderson Cancer Center Hospital, Madrid, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Rojo-Sebastián
authors.affiliation: Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Ángel
authors.initials: Á
authors.lastname: García
authors.affiliation: Department of Pathology and Molecular Genetics/Oncologic Pathology Group, Arnau de Vilanova University Hospital, University of Lleida, IRBLleida, Lleida, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Gatius
authors.affiliation: Department of Pathology and Molecular Genetics/Oncologic Pathology Group, Arnau de Vilanova University Hospital, University of Lleida, IRBLleida, Lleida, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Ruiz
authors.affiliation: Pathology Department, Santa Creu i Sant Pau Hospital, Barcelona, Spain.
authors.forename: Jaime
authors.initials: J
authors.lastname: Prat
authors.affiliation: Translational Medical Oncology, Health Research Institute of Santiago (IDIS), SERGAS, Santiago de Compostela, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: López-López
authors.affiliation: Translational Medical Oncology, Health Research Institute of Santiago (IDIS), SERGAS, Santiago de Compostela, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Abal
authors.affiliation: Biomedical Research Group in Gynecology, Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Gil-Moreno
authors.affiliation: Institut d'Investigacions Biomèdiques de Bellvitge (IDIBELL), Barcelona, Spain.|Departament de Ciències Bàsiques, Universitat Internacional de Catalunya, Barcelona, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Reventós
authors.affiliation: Department of Pathology and Molecular Genetics/Oncologic Pathology Group, Arnau de Vilanova University Hospital, University of Lleida, IRBLleida, Lleida, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Matias-Guiu
authors.affiliation: MD Anderson International Foundation, Madrid, Spain.|Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), Madrid, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Moreno-Bueno
mesh_terms: D018269:Carcinoma, Endometrioid / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry*; D042002:Chromatin Assembly and Disassembly; D019295:Computational Biology; D004252:DNA Mutational Analysis; D004260:DNA Repair; D016889:Endometrial Neoplasms / Q000235:genetics / Q000473:pathology*; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D053842:Microsatellite Instability; D009154:Mutation; D020125:Mutation, Missense; D009215:Myometrium / Q000378:metabolism / Q000473:pathology; D011379:Prognosis
chemical_list: D002843:Chromatin
keywords: DNA repair; chromatin remodelling; endometrioid endometrial carcinoma; massive sequencing; myometrial invasion