Bi-allelic alterations in DNA repair genes underpin homologous recombination DNA repair defects in breast cancer.
J Pathol
; 242(2): 165-177, 2017 06.
Article
em En
| MEDLINE
| ID: mdl-28299801
ABSTRACT
Homologous recombination (HR) DNA repair-deficient (HRD) breast cancers have been shown to be sensitive to DNA repair targeted therapies. Burgeoning evidence suggests that sporadic breast cancers, lacking germline BRCA1/BRCA2 mutations, may also be HRD. We developed a functional ex vivo RAD51-based test to identify HRD primary breast cancers. An integrated approach examining methylation, gene expression, and whole-exome sequencing was employed to ascertain the aetiology of HRD. Functional HRD breast cancers displayed genomic features of lack of competent HR, including large-scale state transitions and specific mutational signatures. Somatic and/or germline genetic alterations resulting in bi-allelic loss-of-function of HR genes underpinned functional HRD in 89% of cases, and were observed in only one of the 15 HR-proficient samples tested. These findings indicate the importance of a comprehensive genetic assessment of bi-allelic alterations in the HR pathway to deliver a precision medicine-based approach to select patients for therapies targeting tumour-specific DNA repair defects. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Mama
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Proteína BRCA1
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Proteína BRCA2
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Distúrbios no Reparo do DNA
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Rad51 Recombinase
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Reparo de DNA por Recombinação
Tipo de estudo:
Diagnostic_studies
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Prognostic_studies
Limite:
Adult
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Aged
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Aged80
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article