Chi-Cheng Huang1,2,3, Yi-Fang Tsai1,2,4, Chun-Yu Liu1,4,5, Pei-Ju Lien1,2, Yen-Shu Lin1,2, Ta-Chung Chao1,4,6, Chin-Jung Feng1,2, Yen-Jen Chen1,2, Jiun-I Lai1,7,8, Nam Nhut Phan9,10,11, Chih-Yi Hsu4,12, Jen-Hwey Chiu1,2,13, Ling-Ming Tseng14,15,16. 1. Comprehensive Breast Center, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan. 2. Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan. 3. Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan. 4. School of Medicine, College of Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan. 5. Division of Transfusion Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. 6. Division of Chemotherapy, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan. 7. Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan. 8. Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan. 9. Bioinformatics Program, Taiwan International Graduate Program, Institute of Information Science, Academia Sinica, Taipei, Taiwan. 10. Graduate Institute of Biomedical Electronics and Bioinformatics, Department of Electrical Engineering, National Taiwan University, Taipei, Taiwan. 11. Bioinformatics and Biostatistics Core, Centre of Genomic and Precision Medicine, National Taiwan University, Taipei, Taiwan. 12. Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. 13. Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan. 14. Comprehensive Breast Center, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan. Lmtseng87@gmail.com. 15. Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan. Lmtseng87@gmail.com. 16. School of Medicine, College of Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan. Lmtseng87@gmail.com.
Abstract
PURPOSE: Deleterious germline BRCA1/2 mutations are among the most highly pathogenic variants in hereditary breast and ovarian cancer syndrome. Recently, genes implicated in homologous recombination repair (HRR) pathways have been investigated extensively. Defective HRR genes may indicate potential clinical benefits from PARP (poly ADP ribose polymerase) inhibitors beyond BRCA1/2 mutations. METHODS: We evaluated the prevalence of BRCA1/2 mutations as well as alterations in HRR genes with targeted sequencing. A total of 648 consecutive breast cancer samples were assayed, and HRR genes were evaluated for prevalence in breast cancer tissues. RESULTS: Among 648 breast cancers, there were 17 truncating and 2 missense mutations in BRCA1 and 45 truncating and 1 missense mutation in BRCA2, impacting 3% and 5% of the study population (collectively altered in 6%) with cooccurrence of BRCA1/2 in 7 breast cancers. On the other hand, HRR genes were altered in 122 (19%) breast cancers, while TBB (Talazoparib Beyond BRCA) trial-interrogated genes (excluding BRCA1/2) were mutated in 107 (17%) patients. Beyond BRCA1/2, the most prevalent HRR mutant genes came from ARID1A (7%), PALB2 (7%), and PTEN (6%). Collectively, 164 (25%) of the 648 Taiwanese breast cancer samples harbored at least one mutation among HRR genes. CONCLUSIONS: The prevalence of BRCA1/2 mutations was far below one tenth, while the prevalence of HRR mutations was much higher and approached one-fourth among Taiwanese breast cancers. Further opportunities to take advantage of defective HRR genes for breast cancer treatment should be sought for the realization of precision medicine.
PURPOSE: Deleterious germline BRCA1/2 mutations are among the most highly pathogenic variants in hereditary breast and ovarian cancer syndrome. Recently, genes implicated in homologous recombination repair (HRR) pathways have been investigated extensively. Defective HRR genes may indicate potential clinical benefits from PARP (poly ADP ribose polymerase) inhibitors beyond BRCA1/2 mutations. METHODS: We evaluated the prevalence of BRCA1/2 mutations as well as alterations in HRR genes with targeted sequencing. A total of 648 consecutive breast cancer samples were assayed, and HRR genes were evaluated for prevalence in breast cancer tissues. RESULTS: Among 648 breast cancers, there were 17 truncating and 2 missense mutations in BRCA1 and 45 truncating and 1 missense mutation in BRCA2, impacting 3% and 5% of the study population (collectively altered in 6%) with cooccurrence of BRCA1/2 in 7 breast cancers. On the other hand, HRR genes were altered in 122 (19%) breast cancers, while TBB (Talazoparib Beyond BRCA) trial-interrogated genes (excluding BRCA1/2) were mutated in 107 (17%) patients. Beyond BRCA1/2, the most prevalent HRR mutant genes came from ARID1A (7%), PALB2 (7%), and PTEN (6%). Collectively, 164 (25%) of the 648 Taiwanese breast cancer samples harbored at least one mutation among HRR genes. CONCLUSIONS: The prevalence of BRCA1/2 mutations was far below one tenth, while the prevalence of HRR mutations was much higher and approached one-fourth among Taiwanese breast cancers. Further opportunities to take advantage of defective HRR genes for breast cancer treatment should be sought for the realization of precision medicine.
Authors: Dana Farengo Clark; Kara N Maxwell; Jacquelyn Powers; David B Lieberman; Jessica Ebrahimzadeh; Jessica M Long; Danielle McKenna; Payal Shah; Angela Bradbury; Jennifer J D Morrissette; Katherine L Nathanson; Susan M Domchek Journal: JCO Precis Oncol Date: 2019-08-19
Authors: Brian A Dougherty; Zhongwu Lai; Darren R Hodgson; Maria C M Orr; Matthew Hawryluk; James Sun; Roman Yelensky; Stuart K Spencer; Jane D Robertson; Tony W Ho; Anitra Fielding; Jonathan A Ledermann; J Carl Barrett Journal: Oncotarget Date: 2017-07-04