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肺转移是三阴性乳腺癌患者死亡的主要原因之一。 2019年4月11日，国际抗癌联盟《国际癌症杂志》在线发表中国复旦大学附属肿瘤医院谢广东、杨海源、马丁、孙艺华、陈海泉、胡欣、江一舟、邵志敏等学者的研究报告，通过结合全基因组测序和功能筛选，确定了三阴性乳腺癌肺转移的基因变化特征，并且确定了改善三阴性乳腺癌患者风险分层的转移相关基因谱。 该前瞻观察研究首先对一例三阴性乳腺癌患者的原发肿瘤和肺转移灶进行全基因组测序，以确定潜在的驱动基因改变。随后，利用基因可读框扩增文库进行体内功能获得筛选，以筛选出可能促进肺转移的候选基因。最后，通过多因素比例风险回归模型，确定三阴性乳腺癌14个候选基因的预后基因谱。 结果，肺转移灶与原发肿瘤相比，染色体3q和8q的拷贝数扩增。通过小鼠肺转移模型，发现染色体3q和8q的14个基因富集。进一步确定并且验证了四联基因谱（ENY2、KCNK9、TNFRSF11B、KCNMB2）可以预测三阴性乳腺癌的无复发生存和肺转移。该研究数据还表明，体外和体内ENY2表达水平提高可以促进三阴性乳腺癌细胞的浸润和肺转移。 因此，该研究结果表明，三阴性乳腺癌肺转移患者染色体3q和8q具有拷贝数扩增的功能基因，并且确定四联功能基因谱，可以有效地将患者分为低复发风险和高复发风险的亚组，有助于对三阴性乳腺癌进行个体化治疗。 Int J Cancer. 2019 Apr 11. [Epub ahead of print] Integration of whole-genome sequencing and functional screening identifies a prognostic signature for lung metastasis in triple-negative breast cancer. Xie G, Yang H, Ma D, Sun Y, Chen H, Hu X, Jiang Y, Shao Z. Fudan University Shanghai Cancer Center; Shanghai Medical College, Fudan University; Institutes of Biomedical Sciences, Fudan University, Shanghai, China. Lung metastasis is one of the leading causes of death for triple-negative breast cancer (TNBC). We sought to characterize the genetic alterations underlying TNBC lung metastases by integrating whole-genome sequencing and functional screening. Further, we aimed to develop a metastasis-related gene signature for TNBC patients to improve risk stratification. In this prospective observational study, we first conducted whole-genome sequencing of paired primary tumor and lung metastasis from one TNBC patient to identify potential genetic driver alterations. An in vivo gain-of-function screening using an amplified open reading frame library was then employed to screen candidate genes promoting lung metastasis. Finally, we applied Cox proportional hazard regression modeling to develop a prognostic gene signature from 14 candidate genes in TNBC. Compared with the primary tumor, copy number amplifications of chromosomes 3q and 8q were identified in the lung metastasis. We discovered an enrichment of 14 genes from chromosomes 3q and 8q in mouse lung metastases model. We further developed and validated a four-gene signature (ENY2, KCNK9, TNFRSF11B and KCNMB2) that predicts recurrence-free survival and lung metastasis in TNBC. Our data also demonstrated that upregulated expression of ENY2 could promote invasion and lung metastasis of TNBC cells both in vitro and in vivo. In conclusion, our study reveals functional genes with copy number amplifications among chromosome 3q and 8q in lung metastasis of TNBC. And we develop a functional gene signature that can effectively stratify patients into low- and high-risk subgroups of recurrence, helping frame personalized treatments for TNBC. KEYWORDS: triple-negative breast cancer; whole-genome sequencing; gain-of-function screening; gene signature; recurrence-free survival PMID: 30977117 DOI: 10.1002/ijc.32329 |
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