Chromatin remodelling and DNA repair genes are frequently mutated in endometrioid endometrial carcinoma

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.Grant sponsor: AECC (Grupos Estables de Investigacion); Grant number: 2011-AECC-GCB 110333; Grant sponsor: Instituto de Salud Carlos III; Grant numbers: PI13/00132, PI16/00134, RETIC-RD12/0036/0007, RETIC-RD12/0036/0035, PI13/01701, RD12/0036/0013, PI14/02043, PI14/01942; Grant sponsor: “CIRIT, Generalitat de Catalunya”; Grant numbers: 2014 SGR 1330, 2014 SGR 138; Grant sponsor:GEIS award 2013; Grant sponsor: “Comunidad de Madrid”; Grant number: S2010/BMD-2303; Grant sponsor: Telemarató; Grant number:TV3 2013; Grant sponsor: AECC Scientific Foundation; Grant sponsor: UAM; Grant number: FPI-UAM 2014; Grant sponsor: Spanish Ministry of Education, Culture and Sports; Grant number: FPU2012-5338; Grant sponsor: Spanish Ministry of Economy and Competitiveness; Grant number: FPDI-2013–18322.Peer Reviewe