@article{749f1923ba1b47dc9a5b48caeff5b371,
title = "Altered regulation of BRCA1 exon 11 splicing is associated with breast cancer risk in carriers of BRCA1 pathogenic variants",
abstract = "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.",
keywords = "BRCA1, breast cancer, isoform, risk, splicing, variant",
author = "GEMO and CIMBA and {Ruiz de Garibay}, Gorka and Ignacio Fernandez-Garcia and Sylvie Mazoyer and {Leme de Calais}, Flavia and Pietro Ameri and Sangeetha Vijayakumar and Haydeliz Martinez-Ruiz and Francesca Damiola and Laure Barjhoux and Mads Thomassen and Andersen, {Lars v.B.} and Carmen Herranz and Francesca Mateo and Luis Palomero and Roderic Esp{\'i}n and Antonio G{\'o}mez and Nadia Garc{\'i}a and Daniel Jimenez and N{\'u}ria Bonifaci and Extremera, {Ana I.} and Julio Casta{\~n}o and Angel Raya and Eduardo Eyras and Puente, {Xose S.} and Joan Brunet and Conxi L{\'a}zaro and Paolo Radice and Barnes, {Daniel R.} and Antoniou, {Antonis C.} and Spurdle, {Amanda B.} and {de la Hoya}, Miguel and Diana Baralle and Barcellos-Hoff, {Mary Helen} and Pujana, {Miquel A.}",
note = "Funding Information: The study of the wild‐type allele was first proposed and led by Dr. Olga Sinilnikova in CIMBA. We dedicate this study to her memory. The paper is also dedicated to Dr. David L. Kleinberg, who contributed to the study of the BRCA1 mouse model. The authors acknowledge Dr. Weifeng Ruan for his contributions to early studies related to this project, the Experimental Pathology Core Laboratory at NYU School of Medicine for tissue sectioning and staining, the VA Medical Center Animal Facility, and Ms. Clara Montesino for help with the animal experiments. The results are partly based upon data generated by the TCGA Research Network ( https://www.cancer.gov/tcga ), and we express our gratitude to the TCGA consortium and coordinators for producing the data and clinical information used in our study. The ICO‐IDIBELL research was supported by the Generalitat de Catalunya (SGR 2017‐449, 2017‐899 and 2017‐1282; PERIS MedPerCan and PFI‐Salut SLT017‐20‐000076; URDCat; and CERCA programme for IDIBELL institutional support), Carlos III Institute of Health (ISCIII), funded by FEDER funds—a way to build Europe—(Ministry of Science, Innovation, and Universities; grants PI16/00563, PI18/01029, PI19/00553, and PI21/01306; CIBERONC and CIBER‐BBN) and Ministry of Economy and Competitiveness‐MINECO (grants RTI2018‐095377‐B‐100 and RD16/0011/0024). G.R.G. was supported by an IDIBELL post‐residency fellowship. The work at NYU was supported by DOD Breast Cancer Research Program funding to D.L.K. (W81XWH‐11‐1‐0779) and M.H.B.‐H. (W81XWH‐11‐1‐780), and a Novartis Investigator‐Initiated Grant to D.L.K. (CSOM230BUS03). The Baralle laboratory is supported by D.B.'s NIHR Research Professorship (RP‐2016‐07‐011). A.B.S. is supported by an NHMRC Investigator Fellowship (APP: 1177524) and P.R. is supported by funds from the Italian Association for Cancer Research (AIRC; IG number 22093). BRCA1 Funding Information: M.A.P. was the recipient of an unrestricted research grant from Roche Pharma for the development of the ProCURE ICO research program. X.S.P. is a cofounder of and has an ownership interest (including stock and patents) in DREAMgenics. Publisher Copyright: {\textcopyright} 2021 Wiley Periodicals LLC",
year = "2021",
doi = "10.1002/humu.24276",
language = "English",
volume = "42",
pages = "1488--1502",
journal = "Human Mutation",
issn = "1059-7794",
publisher = "John Wiley and Sons Inc.",
number = "11",
}