Clinical breast cancer · 2026
Impact of Typical Somatic Gene Mutation Characteristics on Homologous Recombination Deficiency in Breast Cancer.
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Du Jinsui, Duan Chenglong, Zhang Jiaqi, Zhou Yudong, Wang Yalong, Zhu Lizhe, Li Junyi, Zhang Jianing, Pan Yi, Li Danni, Liu Zhihao, Zhang Chenrong, Zhang Yuhan, Ren Yu, Liu Xi, Wang Bin
Аннотация
BACKGROUND: Homologous recombination deficiency (HRD) is an important contributor to genomic instability in breast cancer. This study aimed to characterize the mutational landscape of HRD breast cancer in a Shaanxi cohort and explore its clinicogenomic and immune microenvironment characteristics.
METHODS: Gene mutation profiles were analyzed in 130 breast cancer patients, and HRD status were quantified using Genomic Scar Scores (GSS). Multivariate logistic regression was used to identify clinicogenomic factors associated with HRD status. Immunohistochemistry for AR, CD8, and FOXC1 was further performed in tumor samples from 20 triple-negative breast cancer patients with different mutation patterns to evaluate molecular subtype characteristics.
RESULTS: The most frequently mutated genes in HRD patients were TP53 (61 cases), BRCA (29 cases; BRCA1: 18, BRCA2: 11), and other genes such as FANCA, PTEN. Tumors harboring comutations of TP53 and BRCA exhibited significantly higher GSS compared with tumors without detectable somatic mutations (82.33 vs. 22.25, P < .001). Among HRD-related triple-negative breast cancer, tumors with germline BRCA mutations alone were predominantly classified as basal-like immunosuppressed, whereas TP53-mutated tumors were mainly immunomodulatory. Tumors with co-occurring germline BRCA and TP53 mutations demonstrated higher CD8⁺ T cell infiltration and were primarily classified as the immunomodulatory subtype.
CONCLUSIONS: BRCA and TP53 represent the most common genomic alterations in HRD-associated breast cancer in this cohort. Co-occurring BRCA and TP53 mutations were associated with higher genomic instability and distinct immune-related subtype characteristics in triple-negative breast cancer, highlighting the molecular heterogeneity of HRD-associated tumors.
METHODS: Gene mutation profiles were analyzed in 130 breast cancer patients, and HRD status were quantified using Genomic Scar Scores (GSS). Multivariate logistic regression was used to identify clinicogenomic factors associated with HRD status. Immunohistochemistry for AR, CD8, and FOXC1 was further performed in tumor samples from 20 triple-negative breast cancer patients with different mutation patterns to evaluate molecular subtype characteristics.
RESULTS: The most frequently mutated genes in HRD patients were TP53 (61 cases), BRCA (29 cases; BRCA1: 18, BRCA2: 11), and other genes such as FANCA, PTEN. Tumors harboring comutations of TP53 and BRCA exhibited significantly higher GSS compared with tumors without detectable somatic mutations (82.33 vs. 22.25, P < .001). Among HRD-related triple-negative breast cancer, tumors with germline BRCA mutations alone were predominantly classified as basal-like immunosuppressed, whereas TP53-mutated tumors were mainly immunomodulatory. Tumors with co-occurring germline BRCA and TP53 mutations demonstrated higher CD8⁺ T cell infiltration and were primarily classified as the immunomodulatory subtype.
CONCLUSIONS: BRCA and TP53 represent the most common genomic alterations in HRD-associated breast cancer in this cohort. Co-occurring BRCA and TP53 mutations were associated with higher genomic instability and distinct immune-related subtype characteristics in triple-negative breast cancer, highlighting the molecular heterogeneity of HRD-associated tumors.