Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville.
Department of Medical Oncology, Thomas Jefferson University, Philadelphia.
Ann Oncol. 2017 Sep 1;28(9):2135-2141. doi: 10.1093/annonc/mdx278.
Distant metastasis accounts for 90% of deaths from colorectal cancer (CRC). Genomic heterogeneity has been reported in various solid malignancies, but remains largely under-explored in metastatic CRC tumors, especially in primary to metastatic tumor evolution.
We conducted high-depth whole-exome sequencing in multiple regions of matched primary and metastatic CRC tumors. Using a total of 28 tumor, normal, and lymph node tissues, we analyzed inter- and intra-individual heterogeneity, inferred the tumor subclonal architectures, and depicted the subclonal evolutionary routes from primary to metastatic tumors.
CRC has significant inter-individual but relatively limited intra-individual heterogeneity. Genomic landscapes were more similar within primary, metastatic, or lymph node tumors than across these types. Metastatic tumors exhibited less intratumor heterogeneity than primary tumors, indicating that single-region sequencing may be adequate to identify important metastasis mutations to guide treatment. Remarkably, all metastatic tumors inherited multiple genetically distinct subclones from primary tumors, supporting a possible polyclonal seeding mechanism for metastasis. Analysis of one patient with the trio samples of primary, metastatic, and lymph node tumors supported a mechanism of synchronous parallel dissemination from the primary to metastatic tumors that was not mediated through lymph nodes.
In CRC, metastatic tumors have different but less heterogeneous genomic landscapes than primary tumors. It is possible that CRC metastasis is, at least partly, mediated through a polyclonal seeding mechanism. These findings demonstrated the rationale and feasibility for identifying and targeting primary tumor-derived metastasis-potent subclones for the prediction, prevention, and treatment of CRC metastasis.
结直肠癌（CRC）患者 90%的死亡归因于远处转移。已有研究报道多种实体恶性肿瘤存在基因组异质性，但转移性 CRC 肿瘤中的这种异质性在很大程度上仍未得到充分探索，尤其是在原发灶到转移灶的肿瘤演变过程中。
我们对匹配的原发和转移性 CRC 肿瘤的多个区域进行了深度全外显子组测序。利用总共 28 个肿瘤、正常和淋巴结组织，我们分析了个体内和个体间的异质性，推断了肿瘤亚克隆结构，并描绘了从原发灶到转移灶的亚克隆进化路径。
CRC 存在显著的个体间异质性，但个体内异质性相对有限。原发性、转移性或淋巴结肿瘤的基因组图谱比不同类型肿瘤之间更为相似。转移性肿瘤的肿瘤内异质性低于原发性肿瘤，表明单区域测序可能足以识别重要的转移突变，以指导治疗。值得注意的是，所有转移性肿瘤均从原发性肿瘤中遗传了多个遗传上不同的亚克隆，支持转移可能存在多克隆播种机制。对一名具有原发性、转移性和淋巴结肿瘤三对样本的患者进行分析，支持了原发性肿瘤到转移性肿瘤同步平行播散的机制，而不是通过淋巴结介导的。
在 CRC 中，转移性肿瘤的基因组图谱与原发性肿瘤不同，但异质性较低。CRC 转移至少部分可能是通过多克隆播种机制介导的。这些发现为鉴定和靶向原发性肿瘤衍生的具有转移潜能的亚克隆以预测、预防和治疗 CRC 转移提供了依据和可行性。
