Altered regulation of BRCA1 exon 11 splicing is associated with breast cancer risk in carriers of BRCA1 pathogenic variants.

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Grant Information:	United Kingdom DH_ Department of Health
Contributed Indexing:	Keywords: BRCA1; breast cancer; isoform; risk; splicing; variant
Entry Date(s):	Date Created: 20210822 Date Completed: 20220324 Latest Revision: 20220517
Update Code:	20231215
DOI:	10.1002/humu.24276
PMID:	34420246
Autor:	Ruiz de Garibay G; ProCURE, Oncobell, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain., Fernandez-Garcia I; Department of Radiation Oncology, New York University School of Medicine, New York, New York, USA., Mazoyer S; Equipe GENDEV, INSERM U1028, CNRS UMR5292, Centre de Recherche en Neurosciences de Lyon, Université Lyon 1, Université St Etienne, Lyon, France., Leme de Calais F; School of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK., Ameri P; Department of Radiation Oncology, New York University School of Medicine, New York, New York, USA., Vijayakumar S; Department of Radiation Oncology, New York University School of Medicine, New York, New York, USA., Martinez-Ruiz H; Department of Radiation Oncology, New York University School of Medicine, New York, New York, USA., Damiola F; Department of Biopathology, Pathology Research Platform, Centre Léon Bérard, Lyon, France., Barjhoux L; Department of Biopathology, Pathology Research Platform, Centre Léon Bérard, Lyon, France., Thomassen M; Department of Clinical Genetics, Odense University Hospital, Odense C, Denmark., Andersen LVB; Department of Clinical Genetics, Odense University Hospital, Odense C, Denmark., Herranz C; ProCURE, Oncobell, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain., Mateo F; ProCURE, Oncobell, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain., Palomero L; ProCURE, Oncobell, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain., Espín R; ProCURE, Oncobell, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain., Gómez A; Gene Regulation, Stem Cells and Cancer, Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain., García N; ProCURE, Oncobell, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain., Jimenez D; ProCURE, Oncobell, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain., Bonifaci N; ProCURE, Oncobell, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain., Extremera AI; ProCURE, Oncobell, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain., Castaño J; Regenerative Medicine Program, Bellvitge Institute for Biomedical Research (IDIBELL) and Program for Clinical Translation of Regenerative Medicine in Catalonia (P-CMRC), L'Hospitalet del Llobregat, Barcelona, Spain., Raya A; Regenerative Medicine Program, Bellvitge Institute for Biomedical Research (IDIBELL) and Program for Clinical Translation of Regenerative Medicine in Catalonia (P-CMRC), L'Hospitalet del Llobregat, Barcelona, Spain.; Centre for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain.; Catalan Institution for Research and Advanced Studies, Barcelona, Spain., Eyras E; Catalan Institution for Research and Advanced Studies, Barcelona, Spain.; Department of Genome Sciences, The John Curtin School of Medical Research, EMBL Australia Partner Laboratory Network, Australian National University, Canberra, Australia., Puente XS; Department of Biochemistry and Molecular Biology, University Institute of Oncology, University of Oviedo, Oviedo, Spain.; Biomedical Research Centre in Cancer (CIBERONC), Instituto Salud Carlos III, Madrid, Spain., Brunet J; Hereditary Cancer Program, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, and Girona Biomedical Research Institute (IDIBGI), Girona, Catalonia, Spain., Lázaro C; Biomedical Research Centre in Cancer (CIBERONC), Instituto Salud Carlos III, Madrid, Spain.; Hereditary Cancer Program, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, and Girona Biomedical Research Institute (IDIBGI), Girona, Catalonia, Spain., Radice P; Unit of Molecular Bases of Genetic Risk and Genetic Testing, Research Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Barnes DR; Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK., Antoniou AC; Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK., Spurdle AB; Genetics and Computational Division, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia., de la Hoya M; Biomedical Research Centre in Cancer (CIBERONC), Instituto Salud Carlos III, Madrid, Spain.; Molecular Oncology Laboratory, Hospital Clínico San Carlos, Health Research Institute of the Hospital Clínico San Carlos (IdISSC), Madrid, Spain., Baralle D; School of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.; Wessex Clinical Genetics Service, Southampton University Hospital NHS Trust, Southampton, UK., Barcellos-Hoff MH; Department of Radiation Oncology, New York University School of Medicine, New York, New York, USA.; Department of Radiation Oncology, School of Medicine, University of California San Francisco, San Francisco, California, USA., Pujana MA; ProCURE, Oncobell, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
Jazyk:	angličtina
Zdroj:	Human mutation [Hum Mutat] 2021 Nov; Vol. 42 (11), pp. 1488-1502. Date of Electronic Publication: 2021 Aug 31.
DOI:	10.1002/humu.24276
Abstrakt:	Germline pathogenic variants in BRCA1 confer a high risk of developing breast and ovarian cancer. The BRCA1 exon 11 (formally exon 10) is one of the largest exons and codes for the nuclear localization signals of the corresponding gene product. This exon can be partially or entirely skipped during pre-mRNA splicing, leading to three major in-frame isoforms that are detectable in most cell types and tissue, and in normal and cancer settings. However, it is unclear whether the splicing imbalance of this exon is associated with cancer risk. Here we identify a common genetic variant in intron 10, rs5820483 (NC_000017.11:g.43095106_43095108dup), which is associated with exon 11 isoform expression and alternative splicing, and with the risk of breast cancer, but not ovarian cancer, in BRCA1 pathogenic variant carriers. The identification of this genetic effect was confirmed by analogous observations in mouse cells and tissue in which a loxP sequence was inserted in the syntenic intronic region. The prediction that the rs5820483 minor allele variant would create a binding site for the splicing silencer hnRNP A1 was confirmed by pull-down assays. Our data suggest that perturbation of BRCA1 exon 11 splicing modifies the breast cancer risk conferred by pathogenic variants of this gene. (© 2021 Wiley Periodicals LLC.)
Databáze:	MEDLINE
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