中国乳腺癌精准诊疗再添重要研究成果
大规模并行测序又称深度测序、新一代测序、第二代测序、高通量测序，一次可对几十万甚至几百亿条DNA分子进行多基因序列测定，故已被临床广泛用于肿瘤的诊断和治疗。不过，乳腺癌的现有大规模并行测序数据大多来自西方人群。为了促进中国乳腺癌精准肿瘤学的发展，复旦大学附属肿瘤医院精准肿瘤中心利用自主研发的多基因测序平台，绘制了中国首个千人乳腺癌基因突变图谱，首次系统揭示了中国人群的乳腺癌突变特征，发现了中国乳腺癌特有的精准治疗靶点。
2020年11月10日，英国《自然》旗下《自然通讯》在线发表复旦大学附属肿瘤医院郎冠天、江一舟、杨帆、李小光、裴雨晨、马丁、肖毅、王海、杨云松、国琳玮、卢训西、曹阿勇、凌泓、王中华、余科达、狄根红、李大强、王云锦、胡欣、邵志敏、国家人类基因组南方研究中心暨上海人类基因组研究中心施锦绣、张晨辉、胡鹏晨、黄薇、中国科学院上海高等研究院干细胞与纳米医学研究中心薛梦竹、中国科学院上海营养与健康研究所王鹏、复旦大学生命科学学院郁颖、石乐明等学者的研究报告，利用复旦大学附属肿瘤医院大规模前瞻性临床测序平台，全面分析了中国乳腺癌的临床特征和基因组特征。
该研究于2018年4月1日～2019年4月1日从复旦大学附属肿瘤医院入组单侧乳腺癌女性患者1134例，其中早期乳腺癌术前新辅助治疗患者419例、早期乳腺癌术后患者606例、晚期乳腺癌患者109例，包括难治型晚期三阴性乳腺癌患者23例。首先进行肿瘤活检并采集外周血液，随后进行定制多基因大规模并行测序分析。
结果，1134例乳腺癌患者的突变图谱表明，中国与西方患者相比，激素受体阳性、HER2阴性乳腺癌亚型的临床特征和基因组特征显著不同。该队列的9种致癌信号通路中，p53和Hippo信号通路基因突变比例最高，并且存在2种独有突变和9种共有突变。进一步临床前研究表明，NF2功能丧失突变对于Hippo信号通路靶向治疗可能较敏感。
最后，该研究建立基因测序数据库和精准医学知识库，可供数据更新、分享和分析：
复旦大学乳腺癌临床测序数据库：http://data.3steps.cn/cdataportal/study/summary?id=FUSCC_BRCA_panel_1000
复旦大学乳腺癌精准医学知识库：http://public-data.3steps.cn
因此，该研究为中国肿瘤精准治疗提供了一种先进的方法，并且揭示了可供靶向治疗的中国乳腺癌患者基因突变。
郎冠天
马丁
相关链接
Nat Commun. 2020 Nov 10;11(1):5679.
Characterization of the genomic landscape and actionable mutations in Chinese breast cancers by clinical sequencing.
Guan-Tian Lang, Yi-Zhou Jiang, Jin-Xiu Shi, Fan Yang, Xiao-Guang Li, Yu-Chen Pei, Chen-Hui Zhang, Ding Ma, Yi Xiao, Peng-Chen Hu, Hai Wang, Yun-Song Yang, Lin-Wei Guo, Xun-Xi Lu, Meng-Zhu Xue, Peng Wang, A-Yong Cao, Hong Ling, Zhong-Hua Wang, Ke-Da Yu, Gen-Hong Di, Da-Qiang Li, Yun-Jin Wang, Ying Yu, Le-Ming Shi, Xin Hu, Wei Huang, Zhi-Ming Shao.
Fudan University Shanghai Cancer Center, Shanghai, China; Shanghai Medical College, Fudan University, Shanghai, China; Chinese National Human Genome Center at Shanghai and Shanghai Academy of Science and Technology, Shanghai, China; SARI Center for Stem Cell and Nanomedicine, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, China; Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China; School of Life Sciences and Human Phenome Institute, Fudan University, Shanghai, China.
The remarkable advances in next-generation sequencing technology have enabled the wide usage of sequencing as a clinical tool. To promote the advance of precision oncology for breast cancer in China, here we report a large-scale prospective clinical sequencing program using the Fudan-BC panel, and comprehensively analyze the clinical and genomic characteristics of Chinese breast cancer. The mutational landscape of 1,134 breast cancers reveals that the most significant differences between Chinese and Western patients occurred in the hormone receptor positive, human epidermal growth factor receptor 2 negative breast cancer subtype. Mutations in p53 and Hippo signaling pathways are more prevalent, and 2 mutually exclusive and 9 co-occurring patterns exist among 9 oncogenic pathways in our cohort. Further preclinical investigation partially suggests that NF2 loss-of-function mutations can be sensitive to a Hippo-targeted strategy. We establish a public database (Fudan Portal) and a precision medicine knowledge base for data exchange and interpretation. Collectively, our study presents a leading approach to Chinese precision oncology treatment and reveals potentially actionable mutations in breast cancer.
DOI: 10.1038/s41467-020-19342-3