Genome sequencing enhances the diagnostic yield and expands the genetic landscape of male breast cancer
Purpose: To understand the broader genetic landscape of male breast cancer (MBC), focusing on the utility of genome sequencing (GS) beyond BRCA1/2 (HGNC: 1100, 1101) variants. Methods: Twenty-four patients with MBC underwent a multistep genetic analysis. Initial screening targeted BRCA1/2 variants f...
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Elsevier
2025-01-01
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| Series: | Genetics in Medicine Open |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2949774424010458 |
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| author | Wen Wen Sen Zhao Yiwen Jiang Chengzhu Ou Changyuan Guo Ziqi Jia Jiayi Li Yansong Huang Hengyi Xu Pengming Pu Tongxuan Shang Lin Cong Xiang Wang Nan Wu Jiaqi Liu |
| author_facet | Wen Wen Sen Zhao Yiwen Jiang Chengzhu Ou Changyuan Guo Ziqi Jia Jiayi Li Yansong Huang Hengyi Xu Pengming Pu Tongxuan Shang Lin Cong Xiang Wang Nan Wu Jiaqi Liu |
| author_sort | Wen Wen |
| collection | DOAJ |
| description | Purpose: To understand the broader genetic landscape of male breast cancer (MBC), focusing on the utility of genome sequencing (GS) beyond BRCA1/2 (HGNC: 1100, 1101) variants. Methods: Twenty-four patients with MBC underwent a multistep genetic analysis. Initial screening targeted BRCA1/2 variants followed by GS to identify pathogenic/likely pathogenic germline variants through a 3-tiered classification. Polygenic risk score analysis was further incorporated using a model for female breast cancer with 2666 noncancer controls. Exome sequencing was used to transition from germline to somatic investigations, assessing second-hit variant and mutational signatures. Results: The GS analysis unveiled previously unrecognized pathogenic/likely pathogenic germline variants in BARD1, ATR, BRIP1, and CHEK2 (HGNC: 952, 882, 20473, 16627) among 21 BRCA1/2-negative patients with MBC, elevating the diagnostic yield from 12.5% to 33.0% in all MBC. Elevated average polygenic risk score was noted compared with controls, with a significant correlation to early-onset MBC when combined with high-penetrance germline pathogenic variants (P = 1.10 × 10−4). Exome sequencing analysis further identified significant somatic oncogenic drivers and revealed a dominant mutational signature SBS3 across BRCA1/2-negative samples, reinforcing the contribution of omologous recombination deficiency underlying the MBC development. Conclusion: Our findings extended the MBC genetic spectrum beyond BRCA1/2 and highlighted the intricate interplay of monogenic and polygenic predispositions, presenting a comprehensive MBC genomic profile. |
| format | Article |
| id | doaj-art-3511c51aec3a4338bfa76f5e28cd2e3f |
| institution | Kabale University |
| issn | 2949-7744 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Genetics in Medicine Open |
| spelling | doaj-art-3511c51aec3a4338bfa76f5e28cd2e3f2025-02-04T04:10:43ZengElsevierGenetics in Medicine Open2949-77442025-01-013101899Genome sequencing enhances the diagnostic yield and expands the genetic landscape of male breast cancerWen Wen0Sen Zhao1Yiwen Jiang2Chengzhu Ou3Changyuan Guo4Ziqi Jia5Jiayi Li6Yansong Huang7Hengyi Xu8Pengming Pu9Tongxuan Shang10Lin Cong11Xiang Wang12Nan Wu13Jiaqi Liu14Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; School of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaState Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TXDepartment of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; School of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaState Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; School of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaDepartment of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaDepartment of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaDepartment of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; School of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaDepartment of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; School of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaDepartment of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; School of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaDepartment of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; School of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaDepartment of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; School of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaDepartment of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; School of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaDepartment of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Xiang Wang, 17 Panjiayuannanli, Chaoyang, Beijing 100021, China.State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China; Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing, China; Nan Wu, 1 Shuaifuyuan, Beijing 100730, China.Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Correspondence and requests for materials should be addressed to Jiaqi Liu, 17 Panjiayuannanli, Chaoyang, Beijing 100021, China.Purpose: To understand the broader genetic landscape of male breast cancer (MBC), focusing on the utility of genome sequencing (GS) beyond BRCA1/2 (HGNC: 1100, 1101) variants. Methods: Twenty-four patients with MBC underwent a multistep genetic analysis. Initial screening targeted BRCA1/2 variants followed by GS to identify pathogenic/likely pathogenic germline variants through a 3-tiered classification. Polygenic risk score analysis was further incorporated using a model for female breast cancer with 2666 noncancer controls. Exome sequencing was used to transition from germline to somatic investigations, assessing second-hit variant and mutational signatures. Results: The GS analysis unveiled previously unrecognized pathogenic/likely pathogenic germline variants in BARD1, ATR, BRIP1, and CHEK2 (HGNC: 952, 882, 20473, 16627) among 21 BRCA1/2-negative patients with MBC, elevating the diagnostic yield from 12.5% to 33.0% in all MBC. Elevated average polygenic risk score was noted compared with controls, with a significant correlation to early-onset MBC when combined with high-penetrance germline pathogenic variants (P = 1.10 × 10−4). Exome sequencing analysis further identified significant somatic oncogenic drivers and revealed a dominant mutational signature SBS3 across BRCA1/2-negative samples, reinforcing the contribution of omologous recombination deficiency underlying the MBC development. Conclusion: Our findings extended the MBC genetic spectrum beyond BRCA1/2 and highlighted the intricate interplay of monogenic and polygenic predispositions, presenting a comprehensive MBC genomic profile.http://www.sciencedirect.com/science/article/pii/S2949774424010458Genetic testingGenome sequencingMale breast cancerMutational landscapePolygenic risk score |
| spellingShingle | Wen Wen Sen Zhao Yiwen Jiang Chengzhu Ou Changyuan Guo Ziqi Jia Jiayi Li Yansong Huang Hengyi Xu Pengming Pu Tongxuan Shang Lin Cong Xiang Wang Nan Wu Jiaqi Liu Genome sequencing enhances the diagnostic yield and expands the genetic landscape of male breast cancer Genetics in Medicine Open Genetic testing Genome sequencing Male breast cancer Mutational landscape Polygenic risk score |
| title | Genome sequencing enhances the diagnostic yield and expands the genetic landscape of male breast cancer |
| title_full | Genome sequencing enhances the diagnostic yield and expands the genetic landscape of male breast cancer |
| title_fullStr | Genome sequencing enhances the diagnostic yield and expands the genetic landscape of male breast cancer |
| title_full_unstemmed | Genome sequencing enhances the diagnostic yield and expands the genetic landscape of male breast cancer |
| title_short | Genome sequencing enhances the diagnostic yield and expands the genetic landscape of male breast cancer |
| title_sort | genome sequencing enhances the diagnostic yield and expands the genetic landscape of male breast cancer |
| topic | Genetic testing Genome sequencing Male breast cancer Mutational landscape Polygenic risk score |
| url | http://www.sciencedirect.com/science/article/pii/S2949774424010458 |
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