CRCM, Predictive Oncology team, Inserm, Aix-Marseille Univ, CNRS, Institut Paoli-Calmettes, Marseille, France.
Institute of Pathology, University Hospital Basel, Basel, Switzerland.
Nature. 2019 May;569(7757):560-564. doi: 10.1038/s41586-019-1056-z. Epub 2019 May 22.
Metastasis is the main cause of death for patients with breast cancer. Many studies have characterized the genomic landscape of breast cancer during its early stages. However, there is evidence that genomic alterations are acquired during the evolution of cancers from their early to late stages, and that the genomic landscape of early cancers is not representative of that of lethal cancers. Here we investigated the landscape of somatic alterations in 617 metastatic breast cancers. Nine driver genes (TP53, ESR1, GATA3, KMT2C, NCOR1, AKT1, NF1, RIC8A and RB1) were more frequently mutated in metastatic breast cancers that expressed hormone receptors (oestrogen and/or progesterone receptors; HR) but did not have high levels of HER2 (HER2; n = 381), when compared to early breast cancers from The Cancer Genome Atlas. In addition, 18 amplicons were more frequently observed in HR/HER2 metastatic breast cancers. These cancers showed an increase in mutational signatures S2, S3, S10, S13 and S17. Among the gene alterations that were enriched in HR/HER2 metastatic breast cancers, mutations in TP53, RB1 and NF1, together with S10, S13 and S17, were associated with poor outcome. Metastatic triple-negative breast cancers showed an increase in the frequency of somatic biallelic loss-of-function mutations in genes related to homologous recombination DNA repair, compared to early triple-negative breast cancers (7% versus 2%). Finally, metastatic breast cancers showed an increase in mutational burden and clonal diversity compared to early breast cancers. Thus, the genomic landscape of metastatic breast cancer is enriched in clinically relevant genomic alterations and is more complex than that of early breast cancer. The identification of genomic alterations associated with poor outcome will allow earlier and better selection of patients who require the use of treatments that are still in clinical trials. The genetic complexity observed in advanced breast cancer suggests that such treatments should be introduced as early as possible in the disease course.
转移是乳腺癌患者死亡的主要原因。许多研究已经描述了乳腺癌早期阶段的基因组特征。然而，有证据表明，基因组改变是在癌症从早期到晚期的进化过程中获得的，并且早期癌症的基因组特征并不能代表致命癌症的基因组特征。在这里，我们研究了 617 例转移性乳腺癌中的体细胞改变。在表达激素受体（雌激素和/或孕激素受体；HR）但 HER2 水平不高（HER2；n=381）的转移性乳腺癌中，与癌症基因组图谱中的早期乳腺癌相比，有 9 个驱动基因（TP53、ESR1、GATA3、KMT2C、NCOR1、AKT1、NF1、RIC8A 和 RB1）发生突变的频率更高。此外，在 HR/HER2 转移性乳腺癌中更常观察到 18 个扩增子。这些癌症显示出突变特征 S2、S3、S10、S13 和 S17 的增加。在 HR/HER2 转移性乳腺癌中富集的基因改变中，TP53、RB1 和 NF1 的突变，以及 S10、S13 和 S17，与不良预后相关。与早期三阴性乳腺癌（7%对 2%）相比，转移性三阴性乳腺癌中与同源重组 DNA 修复相关的基因中出现了更多的体细胞双等位基因失活突变。最后，与早期乳腺癌相比，转移性乳腺癌的突变负荷和克隆多样性增加。因此，转移性乳腺癌的基因组特征中富集了具有临床意义的基因组改变，并且比早期乳腺癌更为复杂。鉴定与不良预后相关的基因组改变将允许更早更好地选择需要使用仍处于临床试验阶段的治疗方法的患者。晚期乳腺癌中观察到的遗传复杂性表明，此类治疗应尽早在疾病过程中引入。
