Homologous recombination deficiency derived from whole-genome sequencing predicts platinum response in triple-negative breast cancers.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
07 04 2023
07 04 2023
Historique:
received:
14
04
2022
accepted:
22
03
2023
medline:
11
4
2023
entrez:
7
4
2023
pubmed:
8
4
2023
Statut:
epublish
Résumé
The high frequency of homologous recombination deficiency (HRD) is the main rationale of testing platinum-based chemotherapy in triple-negative breast cancer (TNBC), however, the existing methods to identify HRD are controversial and there is a medical need for predictive biomarkers. We assess the in vivo response to platinum agents in 55 patient-derived xenografts (PDX) of TNBC to identify determinants of response. The HRD status, determined from whole genome sequencing, is highly predictive of platinum response. BRCA1 promoter methylation is not associated with response, in part due to residual BRCA1 gene expression and homologous recombination proficiency in different tumours showing mono-allelic methylation. Finally, in 2 cisplatin sensitive tumours we identify mutations in XRCC3 and ORC1 genes that are functionally validated in vitro. In conclusion, our results demonstrate that the genomic HRD is predictive of platinum response in a large cohort of TNBC PDX and identify alterations in XRCC3 and ORC1 genes driving cisplatin response.
Identifiants
pubmed: 37029129
doi: 10.1038/s41467-023-37537-2
pii: 10.1038/s41467-023-37537-2
pmc: PMC10082194
doi:
Substances chimiques
Cisplatin
Q20Q21Q62J
Platinum
49DFR088MY
BRCA1 Protein
0
BRCA2 Protein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1958Informations de copyright
© 2023. The Author(s).
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