Clinical consequences of BRCA2 hypomorphism
Abstract The tumor suppressor FANCD1/BRCA2 is crucial for DNA homologous recombination repair (HRR). BRCA2 biallelic pathogenic variants result in a severe form of Fanconi anemia (FA) syndrome, whereas monoallelic pathogenic variants cause mainly hereditary breast and ovarian cancer predisposition....
Main Authors: | , , , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Nature Publishing Group
2021-09-01
|
Series: | npj Breast Cancer |
Online Access: | https://doi.org/10.1038/s41523-021-00322-9 |
id |
doaj-f5fbf0683dd64720a1c4fee28554ad68 |
---|---|
record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Laia Castells-Roca Sara Gutiérrez-Enríquez Sandra Bonache Massimo Bogliolo Estela Carrasco Miriam Aza-Carmona Gemma Montalban Núria Muñoz-Subirana Roser Pujol Cristina Cruz Alba Llop-Guevara María J. Ramírez Cristina Saura Adriana Lasa Violeta Serra Orland Diez Judith Balmaña Jordi Surrallés |
spellingShingle |
Laia Castells-Roca Sara Gutiérrez-Enríquez Sandra Bonache Massimo Bogliolo Estela Carrasco Miriam Aza-Carmona Gemma Montalban Núria Muñoz-Subirana Roser Pujol Cristina Cruz Alba Llop-Guevara María J. Ramírez Cristina Saura Adriana Lasa Violeta Serra Orland Diez Judith Balmaña Jordi Surrallés Clinical consequences of BRCA2 hypomorphism npj Breast Cancer |
author_facet |
Laia Castells-Roca Sara Gutiérrez-Enríquez Sandra Bonache Massimo Bogliolo Estela Carrasco Miriam Aza-Carmona Gemma Montalban Núria Muñoz-Subirana Roser Pujol Cristina Cruz Alba Llop-Guevara María J. Ramírez Cristina Saura Adriana Lasa Violeta Serra Orland Diez Judith Balmaña Jordi Surrallés |
author_sort |
Laia Castells-Roca |
title |
Clinical consequences of BRCA2 hypomorphism |
title_short |
Clinical consequences of BRCA2 hypomorphism |
title_full |
Clinical consequences of BRCA2 hypomorphism |
title_fullStr |
Clinical consequences of BRCA2 hypomorphism |
title_full_unstemmed |
Clinical consequences of BRCA2 hypomorphism |
title_sort |
clinical consequences of brca2 hypomorphism |
publisher |
Nature Publishing Group |
series |
npj Breast Cancer |
issn |
2374-4677 |
publishDate |
2021-09-01 |
description |
Abstract The tumor suppressor FANCD1/BRCA2 is crucial for DNA homologous recombination repair (HRR). BRCA2 biallelic pathogenic variants result in a severe form of Fanconi anemia (FA) syndrome, whereas monoallelic pathogenic variants cause mainly hereditary breast and ovarian cancer predisposition. For decades, the co-occurrence in trans with a clearly pathogenic variant led to assume that the other allele was benign. However, here we show a patient with biallelic BRCA2 (c.1813dup and c.7796 A > G) diagnosed at age 33 with FA after a hypertoxic reaction to chemotherapy during breast cancer treatment. After DNA damage, patient cells displayed intermediate chromosome fragility, reduced survival, cell cycle defects, and significantly decreased RAD51 foci formation. With a newly developed cell-based flow cytometric assay, we measured single BRCA2 allele contributions to HRR, and found that expression of the missense allele in a BRCA2 KO cellular background partially recovered HRR activity. Our data suggest that a hypomorphic BRCA2 allele retaining 37–54% of normal HRR function can prevent FA clinical phenotype, but not the early onset of breast cancer and severe hypersensitivity to chemotherapy. |
url |
https://doi.org/10.1038/s41523-021-00322-9 |
work_keys_str_mv |
AT laiacastellsroca clinicalconsequencesofbrca2hypomorphism AT saragutierrezenriquez clinicalconsequencesofbrca2hypomorphism AT sandrabonache clinicalconsequencesofbrca2hypomorphism AT massimobogliolo clinicalconsequencesofbrca2hypomorphism AT estelacarrasco clinicalconsequencesofbrca2hypomorphism AT miriamazacarmona clinicalconsequencesofbrca2hypomorphism AT gemmamontalban clinicalconsequencesofbrca2hypomorphism AT nuriamunozsubirana clinicalconsequencesofbrca2hypomorphism AT roserpujol clinicalconsequencesofbrca2hypomorphism AT cristinacruz clinicalconsequencesofbrca2hypomorphism AT alballopguevara clinicalconsequencesofbrca2hypomorphism AT mariajramirez clinicalconsequencesofbrca2hypomorphism AT cristinasaura clinicalconsequencesofbrca2hypomorphism AT adrianalasa clinicalconsequencesofbrca2hypomorphism AT violetaserra clinicalconsequencesofbrca2hypomorphism AT orlanddiez clinicalconsequencesofbrca2hypomorphism AT judithbalmana clinicalconsequencesofbrca2hypomorphism AT jordisurralles clinicalconsequencesofbrca2hypomorphism |
_version_ |
1717755541022834688 |
spelling |
doaj-f5fbf0683dd64720a1c4fee28554ad682021-09-12T11:35:37ZengNature Publishing Groupnpj Breast Cancer2374-46772021-09-01711910.1038/s41523-021-00322-9Clinical consequences of BRCA2 hypomorphismLaia Castells-Roca0Sara Gutiérrez-Enríquez1Sandra Bonache2Massimo Bogliolo3Estela Carrasco4Miriam Aza-Carmona5Gemma Montalban6Núria Muñoz-Subirana7Roser Pujol8Cristina Cruz9Alba Llop-Guevara10María J. Ramírez11Cristina Saura12Adriana Lasa13Violeta Serra14Orland Diez15Judith Balmaña16Jordi Surrallés17Genome Instability and DNA repair Syndromes Group and Join Unit UAB-IR Sant Pau on Genomic Medicine, Biomedical Research Institute IIB-Sant Pau, Hospital de la Santa Creu i Sant PauHereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital CampusHereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital CampusGenome Instability and DNA repair Syndromes Group and Join Unit UAB-IR Sant Pau on Genomic Medicine, Biomedical Research Institute IIB-Sant Pau, Hospital de la Santa Creu i Sant PauHereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital CampusGenome Instability and DNA repair Syndromes Group and Join Unit UAB-IR Sant Pau on Genomic Medicine, Biomedical Research Institute IIB-Sant Pau, Hospital de la Santa Creu i Sant PauHereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital CampusGenome Instability and DNA repair Syndromes Group and Join Unit UAB-IR Sant Pau on Genomic Medicine, Biomedical Research Institute IIB-Sant Pau, Hospital de la Santa Creu i Sant PauGenome Instability and DNA repair Syndromes Group and Join Unit UAB-IR Sant Pau on Genomic Medicine, Biomedical Research Institute IIB-Sant Pau, Hospital de la Santa Creu i Sant PauExperimental Therapeutics Group, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital CampusExperimental Therapeutics Group, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital CampusGenome Instability and DNA repair Syndromes Group and Join Unit UAB-IR Sant Pau on Genomic Medicine, Biomedical Research Institute IIB-Sant Pau, Hospital de la Santa Creu i Sant PauBreast Cancer and Melanoma Group, Vall d’Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital CampusGenetics Department, Hospital de la Santa Creu i Sant PauExperimental Therapeutics Group, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital CampusHereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital CampusHereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital CampusGenome Instability and DNA repair Syndromes Group and Join Unit UAB-IR Sant Pau on Genomic Medicine, Biomedical Research Institute IIB-Sant Pau, Hospital de la Santa Creu i Sant PauAbstract The tumor suppressor FANCD1/BRCA2 is crucial for DNA homologous recombination repair (HRR). BRCA2 biallelic pathogenic variants result in a severe form of Fanconi anemia (FA) syndrome, whereas monoallelic pathogenic variants cause mainly hereditary breast and ovarian cancer predisposition. For decades, the co-occurrence in trans with a clearly pathogenic variant led to assume that the other allele was benign. However, here we show a patient with biallelic BRCA2 (c.1813dup and c.7796 A > G) diagnosed at age 33 with FA after a hypertoxic reaction to chemotherapy during breast cancer treatment. After DNA damage, patient cells displayed intermediate chromosome fragility, reduced survival, cell cycle defects, and significantly decreased RAD51 foci formation. With a newly developed cell-based flow cytometric assay, we measured single BRCA2 allele contributions to HRR, and found that expression of the missense allele in a BRCA2 KO cellular background partially recovered HRR activity. Our data suggest that a hypomorphic BRCA2 allele retaining 37–54% of normal HRR function can prevent FA clinical phenotype, but not the early onset of breast cancer and severe hypersensitivity to chemotherapy.https://doi.org/10.1038/s41523-021-00322-9 |