Guonan Zhang1, Jie Zhang1, Yi Zhu2, Hong Liu1, Yu Shi1, Kun Mi3, Meiying Li3, Qi Zhao3, Ziyi Huang4, Jianming Huang5. 1. Department of Gynecologic Oncology, Sichuan Cancer Hospital, Chengdu 610041, PR China. 2. Department of Gynecologic Oncology, Sichuan Cancer Hospital, Chengdu 610041, PR China; Department of Ultrasound, Sichuan Cancer Hospital, Chengdu 610041, PR China. 3. Department of Biochemistry & Molecular Biology, Sichuan Cancer Institute, Chengdu 610041, PR China. 4. Department of Bioinformatics, Basic Medical College of Chongqing Medical University, Chongqing, PR China. 5. Department of Biochemistry & Molecular Biology, Sichuan Cancer Institute, Chengdu 610041, PR China. Electronic address: hjianming@yahoo.com.
Abstract
BACKGROUND: Mutations at sites crucial for the interaction between RAD51 and BRC domains impair the ability of BRCA2 homologous recombination. We aimed to clarify whether BRCA2 BRC domain-associated mutation correlates with sensibility of platinum-based chemotherapy and survival in high-grade serous ovarian cancer(HGSOC). METHODS: We identified BRCA2 BRC domain mutations by sequencing PCR-amplified amplicons of genomic DNA isolated from tumor tissues and peripheral blood leukocytes (PBL)in 113 patients with advanced EOC, and assessed platinum-free interval (PFI), progression-free survival (PFS) and overall survival (OS). RESULTS: 21.23% (24 of 113) cases with somatic missense mutation but not germline mutation were identified. Among 24 cases with mutation, 33.3% (8 of 24) cases with nonsense mutation (C-terminal truncation) significantly prolonged median PFI (37 vs 8 months,P=0.000), PFS (43 vs 14 months, p=0.000) and OS (56 vs 31 months, P=0.002); 66.7% (16 of 24) cases with missense mutation also prolonged median PFI (15 vs 8 months, P=0.044), PFS (21 vs 14 months, P=0.049) and OS (38 vs 31 months, P=0.037), compared to those without any mutation. CONCLUSIONS: Somatic mutations in BRCA2 BRC domain confer a higher sensitivity to platinum-based therapy and are associated with a favourable survival in HGSOC.
BACKGROUND: Mutations at sites crucial for the interaction between RAD51 and BRC domains impair the ability of BRCA2 homologous recombination. We aimed to clarify whether BRCA2 BRC domain-associated mutation correlates with sensibility of platinum-based chemotherapy and survival in high-grade serous ovarian cancer(HGSOC). METHODS: We identified BRCA2 BRC domain mutations by sequencing PCR-amplified amplicons of genomic DNA isolated from tumor tissues and peripheral blood leukocytes (PBL)in 113 patients with advanced EOC, and assessed platinum-free interval (PFI), progression-free survival (PFS) and overall survival (OS). RESULTS: 21.23% (24 of 113) cases with somatic missense mutation but not germline mutation were identified. Among 24 cases with mutation, 33.3% (8 of 24) cases with nonsense mutation (C-terminal truncation) significantly prolonged median PFI (37 vs 8 months,P=0.000), PFS (43 vs 14 months, p=0.000) and OS (56 vs 31 months, P=0.002); 66.7% (16 of 24) cases with missense mutation also prolonged median PFI (15 vs 8 months, P=0.044), PFS (21 vs 14 months, P=0.049) and OS (38 vs 31 months, P=0.037), compared to those without any mutation. CONCLUSIONS: Somatic mutations in BRCA2 BRC domain confer a higher sensitivity to platinum-based therapy and are associated with a favourable survival in HGSOC.
Authors: Annamaria Ferrero; Martina Borghese; Stefano Restaino; Andrea Puppo; Giuseppe Vizzielli; Nicoletta Biglia Journal: Int J Environ Res Public Health Date: 2022-04-02 Impact factor: 3.390