English   español  
Por favor, use este identificador para citar o enlazar a este item: http://hdl.handle.net/10261/49242
Título

A high proportion of DNA variants of BRCA1 and BRCA2 is associated with aberrant splicing in breast/ovarian cancer patients

AutorSanz, David J.; Acedo, Alberto ; Infante, Mar ; Durán, Mercedes ; Pérez-Cabornero, Lucía ; Miner, Cristina ; Velasco, Eladio
Fecha de publicaciónmar-2010
EditorAmerican Association for Cancer Research
CitaciónClinical Cancer Research 16(6): 1957-1967 (2010)
Resumen[Purpose]: Most BRCA1/2 mutations are of unknown clinical relevance. An increasing amount of evidence indicates that there can be deleterious effects through the disruption of the splicing process. We have investigated the effect of aberrant splicing of BRCA1/2 on hereditary breast/ovarian cancer (HBOC). [Experimental Design]: DNA variants were analyzed with splicing prediction programs to select putative splicing mutations. Splicing assays of 57 genetic variants were done by lymphocyte reverse transcription-PCR and/or hybrid minigenes in HeLa and nontumor breast epithelial cells. [Results]: Twenty-four BRCA1/2 variants of Spanish HBOC patients were bioinformatically preselected. Functional assays showed that 12 variants induced anomalous splicing patterns, 6 of which accounted for 58.5% of BRCA1 families. To further evaluate the defective splicing of BRCA1/2, we analyzed 31 Breast Cancer Information Core Database (BIC) and two artificial variants that were generated by mutagenesis. Sixteen variants induced different degrees of aberrant splicing. Altogether, anomalous splicing was caused by 28 BRCA1/2 variants of all types, indicating that any DNA change can disrupt pre-mRNA processing. We show that a wide range of regulatory elements can be involved, including the canonical and cryptic splice sites, the polypyrimidine tract, and splicing enhancers/silencers. Twenty mutations were predicted to truncate the BRCA proteins and/or to delete essential domains, thus supporting a role in HBOC. [Conclusions]: An important fraction of DNA variants of BRCA1/2 presents splicing aberrations that may represent a relevant disease-causing mechanism in HBOC. The identification of splicing disruptions by functional assays is a valuable tool to discriminate between benign polymorphisms and pathogenic mutations.
Descripción11 páginas, 3 figuras, 2 tablas.-- et al.-- El pdf del artículo es la versión post-print.
Versión del editorhttp://dx.doi.org/10.1158/1078-0432.CCR-09-2564
URIhttp://hdl.handle.net/10261/49242
DOI10.1158/1078-0432.CCR-09-2564
ISSN1078-0432
E-ISSN1557-3265
Aparece en las colecciones: (IBGM) Artículos
Ficheros en este ítem:
Fichero Descripción Tamaño Formato  
A high proportion of DNA.pdf576,9 kBAdobe PDFVista previa
Visualizar/Abrir
Mostrar el registro completo
 

Artículos relacionados:


NOTA: Los ítems de Digital.CSIC están protegidos por copyright, con todos los derechos reservados, a menos que se indique lo contrario.