期刊
INTERNATIONAL JOURNAL OF CANCER
卷 140, 期 7, 页码 1551-1563出版社
WILEY
DOI: 10.1002/ijc.30573
关键词
endometrioid endometrial carcinoma; massive sequencing; myometrial invasion; chromatin remodelling; DNA repair
类别
资金
- AECC (Grupos Estables de Investigacion) [2011-AECC-GCB 110333]
- Instituto de Salud Carlos III (ISCIII) [PI13/00132, PI16/00134, RETIC-RD12/0036/0007]
- EUFEDER [RETIC-RD12/0036/0035, PI13/01701, RD12/0036/0013, PI14/02043, PI14/01942]
- CIRIT, Generalitat de Catalunya [2014 SGR 1330, 2014 SGR 138]
- GEIS
- Comunidad de Madrid [S2010/BMD-2303, TV3 2013]
- AECC Scientific Foundation
- UAM [FPI-UAM 2014]
- Spanish Ministry of Education, Culture and Sports [FPU2012-5338]
- Spanish Ministry of Economy and Competitiveness [FPDI-2013-18322]
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.
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