中国三阴性乳腺癌遗传变异的临床意义（复旦大学附属肿瘤医院三阴性乳腺癌系列研究）

　　三阴性乳腺癌与其他亚型乳腺癌相比，种系（又称胚系、生殖系、可遗传、先天性）基因变异谱有所不同，并且存在种族差异。不过，中国三阴性乳腺癌患者种系基因变异及其临床意义尚不明确。

　　2020年11月5日，美国《国家癌症研究所杂志》在线发表复旦大学附属肿瘤医院马丁、陈思宇、任金晓、裴雨晨、赵珅、肖毅、徐晓恩、柳光宇、胡欣、余科达、李大强、江一舟、邵志敏、中国科学院上海巴斯德研究所姜从伟和梁小珍等学者的研究报告，探讨了中国三阴性乳腺癌患者种系基因变异的分子特征及其临床意义。

　　该研究利用复旦大学附属肿瘤医院325例三阴性乳腺癌患者全部基因测序数据，确定了三阴性乳腺癌种系变异谱，并分析了其生物学意义和临床意义。

　　结果，其中52例（16.0%）三阴性乳腺癌患者存在至少一种致病或可能致病的种系变异。

　　这些种系变异与未变异的三阴性乳腺癌患者相比：

  • 发病年龄较早

  • 对侧乳腺癌比例较高

  • 基底样免疫抑制信使核糖核酸亚型比例较高

  • 同源重组缺陷突变亚型比例较高

　　54.1%的种系变异可见体细胞等位基因特异失衡，与未失衡相比：

  • 发病年龄较早

  • 同源重组缺陷突变亚型比例较高

　　突变比例最高的基因：

  • BRCA1（7.4%）

  • RAD51D（2.8%）

  • BRCA2（2.2%）

　　中国患者与高加索人或非洲裔美国人患者相比，RAD51D种系变异比例较高，尤其K91fs突变。

　　根据功能分析，中国患者特有的RAD51D种系变异与未变异相比：

  • RAD51D蛋白较不稳定

  • 同源重组缺陷突变亚型比例较高

  • 对PARP抑制剂较敏感

　　因此，该研究结果表明，中国三阴性乳腺癌患者具有独特的种系变异谱，并且显著影响肿瘤的临床特征和分子特征。综合种系与体细胞分析，有助于确定最可能受种系变异影响的三阴性乳腺癌患者，并有助于更精准地进行临床干预。该组中国患者RAD51D种系变异比例较高，可以作为治疗靶点，并用于指导三阴性乳腺癌的精准治疗。

J Natl Cancer Inst. 2020 Nov 5. Online ahead of print.

Molecular features and functional implications of germline variants in triple-negative breast cancer.

Ma D, Chen SY, Ren JX, Pei YC, Jiang CW, Zhao S, Xiao Y, Xu XE, Liu GY, Hu X, Liang XZ, Yu KD, Li DQ, Jiang YZ, Shao ZM.

Fudan University Shanghai Cancer Center, Shanghai, China; hanghai Medical College, Fudan University, Shanghai, China; University of Chinese Academy of Sciences, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China; Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.

BACKGROUND: The germline variant spectrum of triple-negative breast cancer (TNBC) is different from that of other subtypes and has demonstrated ethnic differences. However, the germline variants of TNBC among Chinese patients and its clinical significance remain unclear.

METHODS: Using our multi-omics TNBC cohort (n = 325), we determined the spectrum of germline variants in TNBC and aimed to illustrate their biological and clinical implications.

RESULTS: Overall, 16.0% (52 of 325) of TNBC patients harbored at least one pathogenic or likely pathogenic germline variant. These germline variants were associated with early-onset of TNBC, the occurrence of contralateral breast cancer, the basal-like immune-suppressed mRNA subtype, and the homologous recombination deficiency (HRD) mutation subtype. Somatic allele-specific imbalance was observed in 54.1% of these germline variants, which was correlated with early-onset of breast cancer and elevated HRD. BRCA1 (7.4%), RAD51D (2.8%) and BRCA2 (2.2%) were the genes most frequently mutated. RAD51D germline variants, especially K91fs, were enriched in Chinese patients with TNBC compared to Caucasian and African American patients. The Chinese-specific RAD51D germline variants were functionally associated with the instability of the RAD51D protein, HRD and sensitivity to PARP inhibitors.

CONCLUSIONS: Chinese TNBC patients have a distinct spectrum of germline variants, with a remarkable impact on the clinical and molecular characteristics of the tumor. Integrative germline-somatic analysis may help in identifying TNBC patients who are most likely to be affected by their germline variants and in performing clinical interventions more precisely. The RAD51D variants enriched in our cohort may serve as therapeutic targets and guide precision treatment of TNBC.

KEYWORDS: PARP inhibitor; RAD51D; Triple-negative breast cancer; germline variant; whole-exome sequencing

PMID: 33151324

DOI: 10.1093/jnci/djaa175

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