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Comprehensive genomic profiling of breast cancers characterizes germline-somatic mutation interactions mediating therapeutic vulnerabilities.
- Source :
-
Cell discovery [Cell Discov] 2023 Dec 19; Vol. 9 (1), pp. 125. Date of Electronic Publication: 2023 Dec 19. - Publication Year :
- 2023
-
Abstract
- Germline-somatic mutation interactions are universal and associated with tumorigenesis, but their role in breast cancer, especially in non-Caucasians, remains poorly characterized. We performed large-scale prospective targeted sequencing of matched tumor-blood samples from 4079 Chinese females, coupled with detailed clinical annotation, to map interactions between germline and somatic alterations. We discovered 368 pathogenic germline variants and identified 5 breast cancer DNA repair-associated genes (BCDGs; BRCA1/BRCA2/CHEK2/PALB2/TP53). BCDG mutation carriers, especially those with two-hit inactivation, demonstrated younger onset, higher tumor mutation burden, and greater clinical benefits from platinum drugs, PARP inhibitors, and immune checkpoint inhibitors. Furthermore, we leveraged a multiomics cohort to reveal that clinical benefits derived from two-hit events are associated with increased genome instability and an immune-activated tumor microenvironment. We also established an ethnicity-specific tool to predict BCDG mutation and two-hit status for genetic evaluation and therapeutic decisions. Overall, this study leveraged the large sequencing cohort of Chinese breast cancers, optimizing genomics-guided selection of DNA damaging-targeted therapy and immunotherapy within a broader population.<br /> (© 2023. The Author(s).)
Details
- Language :
- English
- ISSN :
- 2056-5968
- Volume :
- 9
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cell discovery
- Publication Type :
- Academic Journal
- Accession number :
- 38114467
- Full Text :
- https://doi.org/10.1038/s41421-023-00614-3