Metastasis is the major cause of death in breast cancer patients. Although previous large-scale analyses have identified frequently altered genes specific to metastatic breast cancer (MBC) compared with those in primary breast cancer (PBC), metastatic site-specific altered genes in MBC remain largely uncharacterized. Moreover, large-scale analyses are required owing to the low expected frequency of such alterations, likely caused by tumor heterogeneity and late dissemination of breast cancer. To clarify MBC-specific genetic alterations, we integrated publicly available clinical and mutation data of 261 genes, including MBC drivers, from 4268 MBC and 5217 PBC patients from eight different cohorts. We performed meta-analyses and logistic regression analyses to identify MBC-enriched genetic alterations relative to those in PBC across 15 different metastatic site sets. We identified 11 genes that were more frequently altered in MBC samples from pan-metastatic sites, including four genes (SMARCA4, TSC2, ATRX, and AURKA) which were not identified previously. ARID2 mutations were enriched in treatment-naïve de novo and post-treatment MBC samples, compared with that in treatment-naïve PBC samples. In metastatic site-specific analyses, associations of ESR1 with liver metastasis and RICTOR with bone metastasis were significant, regardless of intrinsic subtypes. Among the 15 metastatic site sets, ESR1 mutations were enriched in the liver and depleted in the lymph nodes, whereas TP53 mutations showed an opposite trend. Seven potential MBC driver mutations showed similar preferential enrichment in specific metastatic sites. This large-scale study identified new MBC genetic alterations according to various metastatic sites and highlights their potential role in breast cancer organotropism.

转移是乳腺癌患者死亡的主要原因。尽管以前的大规模分析已经确定了与原发性乳腺癌 (PBC) 相比，转移性乳腺癌 (MBC) 特有的频繁改变的基因，但 MBC 中转移性位点特异性改变的基因在很大程度上仍未得到表征。此外，由于此类改变的预期频率较低，因此需要进行大规模分析，这可能是由肿瘤异质性和乳腺癌晚期扩散引起的。为了阐明 MBC 特定的遗传改变，我们整合了来自 8 个不同队列的 4268 名 MBC 和 5217 名 PBC 患者的 261 个基因（包括 MBC 驱动程序）的公开可用临床和突变数据。我们进行了荟萃分析和逻辑回归分析，以确定相对于 15 个不同转移部位集的 PBC 中富含 MBC 的遗传改变。我们确定了 11 个基因在来自泛转移位点的 MBC 样本中更频繁地改变，包括四个基因（SMARCA4、TSC2、ATRX和AURKA ) 之前未识别。与未经治疗的 PBC 样本相比，ARID2突变在未经治疗的从头和治疗后的 MBC 样本中富集。在转移部位特异性分析中，无论内在亚型如何，ESR1与肝转移和RICTOR与骨转移的关联都是显着的。在 15 个转移位点集中，ESR1突变在肝脏中富集并在淋巴结中耗尽，而TP53突变显示出相反的趋势。七个潜在的 MBC 驱动突变在特定转移部位显示出类似的优先富集。这项大规模研究根据各种转移部位确定了新的 MBC 遗传改变，并强调了它们在乳腺癌器官向性中的潜在作用。