While comparison of primary tumor and metastases has highlighted genomic heterogeneity in colorectal cancer (CRC), previous studies have focused on a single metastatic site or limited genomic testing. Combining data from whole exome and ultra-deep targeted sequencing, we explored possible evolutionary trajectories beyond the status of these mutations, particularly among patient-matched metastatic tumors. Our findings confirm the persistence of known clinically-relevant mutations (e.g., those of RAS family of oncogenes) in CRC primary and metastases, yet reveal that latency and interval systemic therapy affect the course of evolutionary events within metastatic lesions. Specifically, our analysis of patient-matched primary and multiple metastatic lesions, developed over time, showed a similar genetic composition for liver metastatic tumors, which were 21-months apart. This genetic makeup was different from those identified in lung metastases developed before manifestation of the second liver metastasis. These results underscore the role of latency in the evolutionary path of metastatic CRC and may have implications for future treatment options.

中文翻译：

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潜伏期和间隔疗法影响转移性结直肠癌的发展。

虽然原发肿瘤和转移瘤的比较突出了结直肠癌（CRC）的基因组异质性，但先前的研究集中在单个转移位点或有限的基因组检测上。结合来自整个外显子组和超深度靶向测序的数据，我们探索了超出这些突变状态的可能的进化轨迹，尤其是在患者匹配的转移性肿瘤中。我们的发现证实了CRC原发灶和转移灶中已知的临床相关突变（例如，癌基因RAS家族的突变）的持续存在，但揭示了潜伏期和间歇性全身治疗影响转移性病变内进化事件的进程。具体来说，随着时间的推移，我们对患者匹配的原发性和多发性转移性病变的分析显示，肝转移性肿瘤的遗传组成相似，相距21个月。这种遗传构成不同于第二次肝转移表现之前在肺转移中鉴定出的遗传构成。这些结果强调了潜伏期在转移性CRC进化路径中的作用，并可能对将来的治疗选择产生影响。