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Germline mutations of multiple breast cancer-related genes are differentially associated with triple-negative breast cancers and prognostic factors



Genetic testing for BRCA1/2 mutations has become the standard clinical practice. Recent findings suggest the clinical significance of multigene panel testing of BRCA1/2 and other cancer-related genes. However, the clinical features of patients with breast cancer with germline mutations identified using multigene panels remain unclear. In this study, DNA samples from 583 Chinese women with breast cancer were subjected to target sequencing for 54 cancer-related genes using a pre-capture pooling method followed by next-generation sequencing. We identified 79 pathogenic germline mutations in 21 cancer-related genes. Forty-five patients (7.7%) harbored BRCA1/2 mutations, and 38 patients (6.5%) carried pathogenic mutations in the remaining 19 genes. PALB2 was the most commonly (1.2%) mutated gene other than BRCA1/2. Most of the identified pathogenic mutations were novel, suggesting mutation screening by using multigene panel testing is important particularly for non-European populations. Mutations in BRCA1/2 and the other cancer-related genes were differentially associated with clinical features. BRCA1 mutation carriers were strongly associated with triple-negative breast cancer (TNBC), whereas BRCA2 mutation carriers were not. Tumors in BRCA1-mutation carriers had a high histological grade. Patients with BRCA2-mutated breast cancers were likely to develop E-cadherin-negative tumors with bone metastases. Furthermore, mutations in PALB2 were strongly associated with TNBC. We demonstrated the usefulness of multigene panel testing and observed that a substantial proportion of patients with breast cancer had hereditary risk factors. Identifying differential associations between mutation status and clinical features will advance our understanding regarding the pathologies of this heterogeneous disease.

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We are grateful to the participants in this study. The authors would like to thank Enago ( for the English language review. This project was mainly supported by Guangzhou Medical University and National Institute of Genetics (NIG Collaborative Research Program). Hua You is supported by the National Natural Science Foundation of China (81911530169, 81903088, 81670180, 81711540047, and 81850410547). Li Wei is supported by Venture & Innovation Support Program for Chongqing Overseas Returnees (cx2019051). Ke Zheng is supported by the National Natural Science Foundation of China (81202090). Dahai Liu is supported by the National Natural Science Foundation of China (81870307), the University Special Innovative Research Program of Department of Education of Guangdong Province (2017KTSCX189). Ituro Inoue is supported by JSPS and NSFC under the Japan-China Scientific Cooperation Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Correspondence to Ke Zheng or Ituro Inoue or Hua You.

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Hata, C., Nakaoka, H., Xiang, Y. et al. Germline mutations of multiple breast cancer-related genes are differentially associated with triple-negative breast cancers and prognostic factors. J Hum Genet 65, 577–587 (2020).

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