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

Altered regulation of BRCA1 exon 11 splicing is associated with breast cancer risk in carriers of BRCA1 pathogenic variants
Altered regulation of BRCA1 exon 11 splicing is associated with breast cancer risk in carriers of BRCA1 pathogenic variants
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.
BRCA1, breast cancer, isoform, risk, splicing, variant
1059-7794
Ruiz De Garibay, Gorka
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Fernandez‐garcia, Ignacio
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Mazoyer, Sylvie
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Leme De Calais, Flavia
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Ameri, Pietro
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Martinez‐ruiz, Sangeeta Haydeliz
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Damiola, Francesca
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Barjhoux, Laure
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Thomassen, Mads
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Andersen, Lars V. B.
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Herranz, Carmen
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Mateo, Francesca
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Palomero, Luis
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Espin, Roderic
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Gómez, Antonio
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García, Nadia
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Jimenez, Daniel
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Bonifaci, Núria
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Extremera, Ana I.
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Castaño, Julio
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Raya, Angel
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Eyras, Eduardo
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Puente, Xose S.
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Brunet, Joan
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Lázaro, Conxi
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Gemo,
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Cimba,
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Radice, Paolo
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Barnes, Daniel R.
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Antoniou, Antonis C.
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Spurdle, Amanda B.
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Hoya, Miguel
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Baralle, Diana
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Barcellos‐hoff, Mary Helen
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Pujana, Miquel A.
b0b24c36-a004-449c-a1c6-ee75d82b08bf
Ruiz De Garibay, Gorka
9556e1a5-2af7-4aed-b356-c3a452ed20c2
Fernandez‐garcia, Ignacio
5fafe140-4ec9-46f5-a200-404a9f1567ce
Mazoyer, Sylvie
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Leme De Calais, Flavia
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Ameri, Pietro
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Martinez‐ruiz, Sangeeta Haydeliz
babb9250-afe7-4716-b762-32e940700ce7
Damiola, Francesca
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Barjhoux, Laure
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Thomassen, Mads
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Andersen, Lars V. B.
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Herranz, Carmen
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Mateo, Francesca
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Palomero, Luis
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Espin, Roderic
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Gómez, Antonio
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García, Nadia
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Jimenez, Daniel
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Bonifaci, Núria
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Extremera, Ana I.
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Castaño, Julio
a5ff26ed-697a-4ac9-8bf9-98a1e8398c5a
Raya, Angel
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Eyras, Eduardo
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Puente, Xose S.
1884333a-c645-46a9-8600-4469fd05c9b0
Brunet, Joan
802a3fdd-e1e0-4ee0-a7b6-43a4adf67f13
Lázaro, Conxi
efadc95f-3c47-4aeb-8402-26005ff9d628
Gemo,
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Cimba,
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Radice, Paolo
d5bff2d9-ed03-4a8e-a9ca-f896a1666e2c
Barnes, Daniel R.
eea80956-9c62-413a-b5fa-4d6df6d25f5d
Antoniou, Antonis C.
65739e70-823d-4acd-b99a-12c7b5521f34
Spurdle, Amanda B.
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Hoya, Miguel
8e170da0-2396-4f84-ba15-14fa2ad62fb2
Baralle, Diana
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Barcellos‐hoff, Mary Helen
59913d0a-d751-4420-958a-e0fa3cebf94a
Pujana, Miquel A.
b0b24c36-a004-449c-a1c6-ee75d82b08bf

Ruiz De Garibay, Gorka, Fernandez‐garcia, Ignacio, Mazoyer, Sylvie, Leme De Calais, Flavia, Ameri, Pietro, Martinez‐ruiz, Sangeeta Haydeliz, Damiola, Francesca, Barjhoux, Laure, Thomassen, Mads, Andersen, Lars V. B., Herranz, Carmen, Mateo, Francesca, Palomero, Luis, Espin, Roderic, Gómez, Antonio, García, Nadia, Jimenez, Daniel, Bonifaci, Núria, Extremera, Ana I., Castaño, Julio, Raya, Angel, Eyras, Eduardo, Puente, Xose S., Brunet, Joan, Lázaro, Conxi, Gemo, , Cimba, , Radice, Paolo, Barnes, Daniel R., Antoniou, Antonis C., Spurdle, Amanda B., Hoya, Miguel, Baralle, Diana, Barcellos‐hoff, Mary Helen and Pujana, Miquel A. (2021) Altered regulation of BRCA1 exon 11 splicing is associated with breast cancer risk in carriers of BRCA1 pathogenic variants. Human Mutation. (doi:10.1002/humu.24276).

Record type: Article

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.

Text
RuizdeGaribay_MainText_072321 - Accepted Manuscript
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More information

Accepted/In Press date: 19 August 2021
e-pub ahead of print date: 22 August 2021
Keywords: BRCA1, breast cancer, isoform, risk, splicing, variant

Identifiers

Local EPrints ID: 451037
URI: http://eprints.soton.ac.uk/id/eprint/451037
ISSN: 1059-7794
PURE UUID: bb3cd985-ba17-4074-a8a7-6b52e0130307
ORCID for Diana Baralle: ORCID iD orcid.org/0000-0003-3217-4833

Catalogue record

Date deposited: 03 Sep 2021 16:33
Last modified: 22 Sep 2021 01:40

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Contributors

Author: Gorka Ruiz De Garibay
Author: Ignacio Fernandez‐garcia
Author: Sylvie Mazoyer
Author: Flavia Leme De Calais
Author: Pietro Ameri
Author: Sangeeta Haydeliz Martinez‐ruiz
Author: Francesca Damiola
Author: Laure Barjhoux
Author: Mads Thomassen
Author: Lars V. B. Andersen
Author: Carmen Herranz
Author: Francesca Mateo
Author: Luis Palomero
Author: Roderic Espin
Author: Antonio Gómez
Author: Nadia García
Author: Daniel Jimenez
Author: Núria Bonifaci
Author: Ana I. Extremera
Author: Julio Castaño
Author: Angel Raya
Author: Eduardo Eyras
Author: Xose S. Puente
Author: Joan Brunet
Author: Conxi Lázaro
Author: Gemo
Author: Cimba
Author: Paolo Radice
Author: Daniel R. Barnes
Author: Antonis C. Antoniou
Author: Amanda B. Spurdle
Author: Miguel Hoya
Author: Diana Baralle ORCID iD
Author: Mary Helen Barcellos‐hoff
Author: Miquel A. Pujana

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