RESUMEN
Uterine leiomyomata (UL) are the most common neoplasms of the female reproductive tract and primary cause for hysterectomy, leading to considerable morbidity and high economic burden. Here we conduct a GWAS meta-analysis in 35,474 cases and 267,505 female controls of European ancestry, identifying eight novel genome-wide significant (P < 5 × 10-8) loci, in addition to confirming 21 previously reported loci, including multiple independent signals at 10 loci. Phenotypic stratification of UL by heavy menstrual bleeding in 3409 cases and 199,171 female controls reveals genome-wide significant associations at three of the 29 UL loci: 5p15.33 (TERT), 5q35.2 (FGFR4) and 11q22.3 (ATM). Four loci identified in the meta-analysis are also associated with endometriosis risk; an epidemiological meta-analysis across 402,868 women suggests at least a doubling of risk for UL diagnosis among those with a history of endometriosis. These findings increase our understanding of genetic contribution and biology underlying UL development, and suggest overlapping genetic origins with endometriosis.
Asunto(s)
Endometriosis/genética , Leiomioma/genética , Neoplasias Uterinas/genética , Adulto , Proteínas de la Ataxia Telangiectasia Mutada/genética , Endometriosis/epidemiología , Femenino , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Estudio de Asociación del Genoma Completo , Humanos , Leiomioma/complicaciones , Leiomioma/epidemiología , Análisis de la Aleatorización Mendeliana , Menorragia/etiología , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Modelos de Riesgos Proporcionales , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/genética , Transducción de Señal , Telomerasa/genética , Neoplasias Uterinas/complicaciones , Neoplasias Uterinas/epidemiología , Población Blanca/genéticaRESUMEN
BACKGROUND: Kinase module of Mediator complex ('CDK8 submodule') consists of four subunits: CDK8, Cyclin C, MED12, and MED13. Recently, we reported recurrent MED12 mutations in 70% of uterine leiomyomas. The aim of this study was to analyse whether mutations in other components of the module contribute to the development of these lesions. METHODS: Mutation screening of altogether 70 MED12 mutation-negative uterine leiomyomas was carried out by direct sequencing. RESULTS: None of the tumours displayed somatic mutations in the coding regions of CDK8/CDK19, CCNC, or MED13. CONCLUSIONS: Mutations in CDK8/CDK19, CCNC, and MED13 do not frequently contribute to genesis of uterine leiomyomas.
Asunto(s)
Leiomioma/genética , Complejo Mediador/genética , Neoplasias Uterinas/genética , Ciclina C/genética , Quinasa 8 Dependiente de Ciclina/genética , Quinasas Ciclina-Dependientes/genética , Análisis Mutacional de ADN , Femenino , Pruebas Genéticas , HumanosRESUMEN
BACKGROUND: Mediator complex participates in transcriptional regulation by connecting regulatory DNA sequences to the RNA polymerase II initiation complex. Recently, we discovered through exome sequencing that as many as 70% of uterine leiomyomas harbour specific mutations in exon 2 of mediator complex subunit 12 (MED12). In this work, we examined the role of MED12 exon 2 mutations in other tumour types. METHODS: The frequency of MED12 exon 2 mutations was analysed in altogether 1158 tumours by direct sequencing. The tumour spectrum included mesenchymal tumours (extrauterine leiomyomas, endometrial polyps, lipomas, uterine leiomyosarcomas, other sarcomas, gastro-intestinal stromal tumours), hormone-dependent tumours (breast and ovarian cancers), haematological malignancies (acute myeloid leukaemias, acute lymphoid leukaemias, myeloproliferative neoplasms), and tumours associated with abnormal Wnt-signalling (colorectal cancers (CRC)). RESULTS: Five somatic alterations were observed: three in uterine leiomyosarcomas (3/41, 7%; Gly44Ser, Ala38_Leu39ins7, Glu35_Leu36delinsVal), and two in CRC (2/392, 0.5%; Gly44Cys, Ala67Val). CONCLUSION: Somatic MED12 exon 2 mutations were observed in uterine leiomyosarcomas, suggesting that a subgroup of these malignant tumours may develop from a leiomyoma precursor. Mutations in CRC samples indicate that MED12 may, albeit rarely, contribute to CRC tumorigenesis.