title: BRCA1 Alternative splicing landscape in breast tissue samples.
abstract: BACKGROUND
  BRCA1 is a key protein in cell network, involved in DNA repair pathways and cell cycle. Recently, the ENIGMA consortium has reported a high number of alternative splicing (AS) events at this locus in blood-derived samples. However, BRCA1 splicing pattern in breast tissue samples is unknown. Here, we provide an accurate description of BRCA1 splicing events distribution in breast tissue samples.
  
  
  METHODS
  BRCA1 splicing events were scanned in 70 breast tumor samples, 4 breast samples from healthy individuals and in 72 blood-derived samples by capillary electrophoresis (capillary EP). Molecular subtype was identified in all tumor samples. Splicing events were considered predominant if their relative expression level was at least the 10% of the full-length reference signal.
  
  
  RESULTS
  54 BRCA1 AS events were identified, 27 of them were annotated as predominant in at least one sample. Δ5q, Δ13, Δ9, Δ5 and ▼1aA were significantly more frequently annotated as predominant in breast tumor samples than in blood-derived samples. Predominant splicing events were, on average, more frequent in tumor samples than in normal breast tissue samples (P = 0.010). Similarly, likely inactivating splicing events (PTC-NMDs, Non-Coding, Δ5 and Δ18) were more frequently annotated as predominant in tumor than in normal breast samples (P = 0.020), whereas there were no significant differences for other splicing events (No-Fs) frequency distribution between tumor and normal breast samples (P = 0.689).
  
  
  CONCLUSIONS
  Our results complement recent findings by the ENIGMA consortium, demonstrating that BRCA1 AS, despite its tremendous complexity, is similar in breast and blood samples, with no evidences for tissue specific AS events. Further on, we conclude that somatic inactivation of BRCA1 through spliciogenic mutations is, at best, a rare mechanism in breast carcinogenesis, albeit our data detects an excess of likely inactivating AS events in breast tumor samples.
authors.affiliation: Molecular Oncology Laboratoy, Instituto de Investigación Sanitaria San Carlos. Center affiliated to the Red Temática de Investigación Cooperativa (RD12/0036/006), Instituto Carlos III, Spanish Ministry of Economy and Competitivy, 28040, Madrid, Spain. atocha10@hotmail.com.|Medical Oncology Department, Hospital Puerta de Hierro, Madrid, Spain. atocha10@hotmail.com.|Breast Cancer and Systems Biology Unit, Translational Research Laboratory, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Instituto Carlos III, Spanish Ministry of Economy and Competitivy, Barcelona, 08908, Spain. atocha10@hotmail.com.
authors.forename: Atocha
authors.initials: A
authors.lastname: Romero
authors.affiliation: Computational Genomics Department, Centro de Investigación Príncipe Felipe, Valencia, Spain. fgarcia@cipf.es.|Breast Cancer and Systems Biology Unit, Translational Research Laboratory, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Instituto Carlos III, Spanish Ministry of Economy and Competitivy, Barcelona, 08908, Spain. fgarcia@cipf.es.
authors.forename: Francisco
authors.initials: F
authors.lastname: García-García
authors.affiliation: Molecular Oncology Laboratoy, Instituto de Investigación Sanitaria San Carlos. Center affiliated to the Red Temática de Investigación Cooperativa (RD12/0036/006), Instituto Carlos III, Spanish Ministry of Economy and Competitivy, 28040, Madrid, Spain. irenelopezperolio@gmail.com.|Breast Cancer and Systems Biology Unit, Translational Research Laboratory, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Instituto Carlos III, Spanish Ministry of Economy and Competitivy, Barcelona, 08908, Spain. irenelopezperolio@gmail.com.
authors.forename: Irene
authors.initials: I
authors.lastname: López-Perolio
authors.affiliation: Breast Cancer and Systems Biology Unit, Translational Research Laboratory, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Instituto Carlos III, Spanish Ministry of Economy and Competitivy, Barcelona, 08908, Spain. gorkargp@hotmail.com.
authors.forename: Gorka
authors.initials: G
authors.lastname: Ruiz de Garibay
authors.affiliation: Breast Cancer and Systems Biology Unit, Translational Research Laboratory, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Instituto Carlos III, Spanish Ministry of Economy and Competitivy, Barcelona, 08908, Spain. jagsaenz@yahoo.com.|Medical Oncology Department. Hospital Clínico San Carlos. Department of Medicine. Faculty of Medicine, Universidad Complutense Madrid, Madrid, Spain. jagsaenz@yahoo.com.
authors.forename: José A
authors.initials: JA
authors.lastname: García-Sáenz
authors.affiliation: Molecular Oncology Laboratoy, Instituto de Investigación Sanitaria San Carlos. Center affiliated to the Red Temática de Investigación Cooperativa (RD12/0036/006), Instituto Carlos III, Spanish Ministry of Economy and Competitivy, 28040, Madrid, Spain. pilar_garre@hotmail.com.|Breast Cancer and Systems Biology Unit, Translational Research Laboratory, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Instituto Carlos III, Spanish Ministry of Economy and Competitivy, Barcelona, 08908, Spain. pilar_garre@hotmail.com.
authors.forename: Pilar
authors.initials: P
authors.lastname: Garre
authors.affiliation: Molecular Oncology Laboratoy, Instituto de Investigación Sanitaria San Carlos. Center affiliated to the Red Temática de Investigación Cooperativa (RD12/0036/006), Instituto Carlos III, Spanish Ministry of Economy and Competitivy, 28040, Madrid, Spain. patry_8_lna@hotmail.com.|Breast Cancer and Systems Biology Unit, Translational Research Laboratory, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Instituto Carlos III, Spanish Ministry of Economy and Competitivy, Barcelona, 08908, Spain. patry_8_lna@hotmail.com.
authors.forename: Patricia
authors.initials: P
authors.lastname: Ayllón
authors.affiliation: Breast Cancer and Systems Biology Unit, Translational Research Laboratory, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Instituto Carlos III, Spanish Ministry of Economy and Competitivy, Barcelona, 08908, Spain. ebarjonilla@hotmail.com.|Plastic Surgery Department, Hospital Clínico San Carlos, Madrid, Spain. ebarjonilla@hotmail.com.
authors.forename: Esperanza
authors.initials: E
authors.lastname: Benito
authors.affiliation: Computational Genomics Department, Centro de Investigación Príncipe Felipe, Valencia, Spain. jdopazo@cipf.es.|Breast Cancer and Systems Biology Unit, Translational Research Laboratory, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Instituto Carlos III, Spanish Ministry of Economy and Competitivy, Barcelona, 08908, Spain. jdopazo@cipf.es.|Functional Genomics Node, INB, CIPF, Valencia, Spain. jdopazo@cipf.es.|Centre for Biomedical Network Research on Rare Diseases (CIBERER), Valencia, Spain. jdopazo@cipf.es.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Dopazo
authors.affiliation: Molecular Oncology Laboratoy, Instituto de Investigación Sanitaria San Carlos. Center affiliated to the Red Temática de Investigación Cooperativa (RD12/0036/006), Instituto Carlos III, Spanish Ministry of Economy and Competitivy, 28040, Madrid, Spain. eduardo.diazrubio@salud.madrid.org.|Breast Cancer and Systems Biology Unit, Translational Research Laboratory, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Instituto Carlos III, Spanish Ministry of Economy and Competitivy, Barcelona, 08908, Spain. eduardo.diazrubio@salud.madrid.org.|Medical Oncology Department. Hospital Clínico San Carlos. Department of Medicine. Faculty of Medicine, Universidad Complutense Madrid, Madrid, Spain. eduardo.diazrubio@salud.madrid.org.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Díaz-Rubio
authors.affiliation: Molecular Oncology Laboratoy, Instituto de Investigación Sanitaria San Carlos. Center affiliated to the Red Temática de Investigación Cooperativa (RD12/0036/006), Instituto Carlos III, Spanish Ministry of Economy and Competitivy, 28040, Madrid, Spain. trinidad.caldes@salud.madrid.org.|Breast Cancer and Systems Biology Unit, Translational Research Laboratory, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Instituto Carlos III, Spanish Ministry of Economy and Competitivy, Barcelona, 08908, Spain. trinidad.caldes@salud.madrid.org.
authors.forename: Trinidad
authors.initials: T
authors.lastname: Caldés
authors.affiliation: Molecular Oncology Laboratoy, Instituto de Investigación Sanitaria San Carlos. Center affiliated to the Red Temática de Investigación Cooperativa (RD12/0036/006), Instituto Carlos III, Spanish Ministry of Economy and Competitivy, 28040, Madrid, Spain. mdhoya@hotmail.com.|Breast Cancer and Systems Biology Unit, Translational Research Laboratory, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Instituto Carlos III, Spanish Ministry of Economy and Competitivy, Barcelona, 08908, Spain. mdhoya@hotmail.com.
authors.forename: Miguel
authors.initials: M
authors.lastname: de la Hoya
mesh_terms: D017398:Alternative Splicing; D001706:Biopsy; D001940:Breast / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D020868:Gene Silencing; D019398:Genes, BRCA1; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D060787:Neoplasm Grading