Splicing y Susceptibilidad Genética a Cáncer
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Integrantes
Integrantes
Investigador Principal:
Eladio Andrés Velasco-Sampedro
Investigadoras Doctoras
Elena Bueno-Martínez
Lara Sanoguera-Miralles
Técnico de Laboratorio:
Alicia García- Álvarez
Breve descripción del grupo
Our interest is focused on Hereditary Breast and Ovarian Cancer (HBOC) that is characterized by a high genetic heterogeneity. Loss-of-function variants in at least 8 genes (BRCA1, BRCA2, PALB2, BARD1, RAD51C, RAD51D, ATM, and CHEK2) have been recently reported with a significant association with breast cancer risk.
Splicing is a central process of gene expression whereby introns are excised and exons are joined sequentially. Intron removal is guided by a large number of splicing factors, ribonucleoproteins and a complex array of sequences including acceptor and donor sites, polypyrimidine tract and branch point, as well as exonic and intronic splicing enhancers and silencers that stimulate or repress exon inclusion into the mature mRNA, respectively. Consequently, all these elements are potential targets of spliceogenic variants.These alterations remain often hidden as patient RNA assays to characterize them are not available.Our main line of research aims to investigate the role of mis-splicing of breast cancer genes in HBOC. Hybrid minigenes in splicing reporter plasmid are our main tool of the laboratory. They constitute a useful technology for both, the basic knowledge of splicing regulatory mechanisms and the study of the correlation between mutation, defective splicing and disease. In fact, we have developed and patented a new splicing vector, pSAD (Splicing And Disease; patent #P201231427: “Plasmid pSAD for splicing functional assays”), where there have been constructed a complete set of Breast Cancer minigenes, including BRCA2, BRCA1, CHEK2, PALB2, ATM, RAD51C, RAD51D, TP53 and BARD1.Therefore, we can potentially assay any candidate variant in these genes to study its impact on splicing. Actually, we have already analyzed ~900 variants by minigene assays.
We have also set up a splicing-minigene facility (http://www.ibgm.med.uva.es/servicios/servicio-de-splicing-minigenes/) to study any human gene under the splicing viewpoint. In fact, we have already developed minigenes of MLH1 (Lynch syndrome), SERPINA1 (Severe Alpha-1 Antitrypsin Deficiency), COL1A1 (Osteogenesis Imperfecta), CHD7 (Charge Syndrome, Intellectual Disability), GRN (Frontotemporal Dementia), UGT1A1 (Gilbert’s and Crigler-Najjar syndromes), TRPM4 (colorectal cancer) and TP53 (Li-Fraumeni Syndrome and breast cancer susceptibility).
Hitos más relevantes
Canson DM, Wiggins GAR, Velasco-Sampedro EA, Pearson JF, Walker LC, Spurdle AB. Evidence-based recommendations for application of construct-based splicing data in clinical variant classification. Genome Med. (2026). https://doi.org/10.1186/s13073-026-01746-3.
Llinares-Burguet I, Sanoguera-Miralles L, Bueno-Martínez E, Esteban-Sanchez A, Romano-Medina D, Ramadane-Morchadi L, García-Álvarez A, Pérez-Segura P, Easton DF, Devilee P, Vreeswijk MPG, de la Hoya M, Velasco-Sampedro EA. Experimental Mis-Splicing Assessment and ACMG/AMP-Guided Classification of 47 ATM Splice-Site Variants. Int J Mol Sci. 2026 Jan 12;27(2):765. doi: 10.3390/ijms27020765. PMID: 41596415.
Llinares-Burguet I, Sanoguera-Miralles L, Bueno-Martínez E, García-Álvarez A, Valenzuela-Palomo A, Pérez-Segura P, de la Hoya M, Velasco-Sampedro EA. Generation of functional noncanonical donor splice sites by +2T variants in breast cancer susceptibility genes: impact on clinical interpretation. J Pathol. 2026 Feb;268(2):150-163. doi: 10.1002/path.6497. PMID: 41230741.
Llinares-Burguet I, Sanoguera-Miralles L, García-Álvarez A, Esteban-Sánchez A, Caloca MJ, de la Hoya M, Bueno-Martínez E, Velasco-Sampedro EA. Unproductive alternative splicing of ATM exon 7: mapping of critical regulatory elements and identification of 34 spliceogenic variants. J Mol Med (Berl). 2025 Nov;103(11-12):1447-1460. doi: 10.1007/s00109-025-02595-0. PMID: 40974429.
Fortuno C, Llinares-Burguet I, Canson DM, de la Hoya M, Bueno-Martínez E, Sanoguera-Miralles L, Caldes S, James PA, Velasco-Sampedro EA, Spurdle AB. Exploring the role of splicing in TP53 variant pathogenicity through predictions and minigene assays. Hum Genomics. 2025 8;19(1):2. doi: 10.1186/s40246-024-00714-5. PMID: 39780207.
Canson DM, Llinares-Burguet I, Fortuno C, Sanoguera-Miralles L, Bueno-Martínez E, de la Hoya M, Spurdle AB, Velasco-Sampedro EA. TP53 minigene analysis of 161 sequence changes provides evidence for role of spatial constraint and regulatory elements on variant-induced splicing impact. NPJ Genom Med. 2025;10:37. doi: 10.1038/s41525-025-00498-0. PMID: 40341019.
Proyectos destacados
Título del proyecto: Desregulación del splicing de macroexones y microexones en genes de susceptibilidad a cáncer de mama (PI23/00047).
Duración: 2024 - 2026.
Entidad financiadora: Ministerio de Ciencia, Innovación y Universidades, Instituto de Salud Carlos III. Proyectos de I+D+i en salud, AES 2021-2023. Cofinanciado por la Unión Europea.
Presupuesto: 91.250 €.
Investigador Principal: Eladio Andrés Velasco-Sampedro.
Proyecto PI23/00047 financiado por:
2021-2023 Proyecto de investigación financiado por el Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (PI20/00225) (93.170,00€).
"Splicing regulation of alternative and atypical exons of breast cancer genes in physiological and DNA damage conditions: implications in disease susceptibility"
IP: Eladio A. Velasco Sampedro.
2018-2020 Proyecto de investigación financiado por el Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (PI17/00227) (99.220,00€).
"Aberrant splicing in hereditary breast cancer: Functional analysis of susceptibility genes by hybrid minigenes".
IP: Eladio A. Velasco Sampedro.
2015-2021 Proyecto de investigación financiado por la Comisión Europea, Proyecto Europeo H2020 (634935) (75.000,00€).
"Breast Cancer Risk after Diagnostic Gene Sequencing (BRIDGES)".
IP: Eladio A. Velasco Sampedro.
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