Single-cell whole-exome sequencing (scWES) is a powerful approach for deciphering intratumor heterogeneity and identifying cancer drivers. So far, however, simultaneous analysis of single nucleotide variants (SNVs) and copy number variations (CNVs) of a single cell has been challenging. By analyzing SNVs and CNVs simultaneously in bulk and single cells of premalignant tissues and tumors from mouse and human BRCA1-associated breast cancers, we discover an evolution process through which the tumors initiate from cells with SNVs affecting driver genes in the premalignant stage and malignantly progress later via CNVs acquired in chromosome regions with cancer driver genes. These events occur randomly and hit many putative cancer drivers besides p53 to generate unique genetic and pathological features for each tumor. Upon this, we finally identify a tumor metastasis suppressor Plekha5, whose deficiency promotes cancer metastasis to the liver and/or lung.

单细胞全外显子组测序 (scWES) 是破译肿瘤内异质性和识别癌症驱动因素的有力方法。然而，到目前为止，同时分析单个细胞的单核苷酸变异 (SNV) 和拷贝数变异 (CNV) 一直具有挑战性。通过同时分析来自小鼠和人类BRCA1相关乳腺癌的癌前组织和肿瘤的大块细胞和单细胞中的 SNV 和 CNV ，我们发现了一个进化过程，通过该过程，肿瘤从具有影响驱动基因的 SNV 的细胞开始并恶性进展后来通过在具有癌症驱动基因的染色体区域获得的 CNV。这些事件随机发生并影响除p53之外的许多假定的癌症驱动因素为每个肿瘤生成独特的遗传和病理特征。在此基础上，我们最终确定了肿瘤转移抑制因子Plekha5，其缺陷会促进癌症转移到肝脏和/或肺。