Illuminating the evolutionary history of colorectal cancer metastasis: basic principles and clinical applications

背景资料。转移到重要器官是大多数癌症患者的死亡原因。尽管它 对于了解全身性疾病的演变具有非常重要的临床意义，转移仍然是 对癌症进展的了解最少的方面。我们仍然没有许多基本问题的答案 问题：转移发现者是从原发肿瘤中随机选择的细胞吗？ 实质上相等的转移能力？或者，专门化的转移克隆是否进化，也许是在中期 像区域淋巴结一样的避难所空间，然后继续殖民遥远的身体部位？是转移性肿瘤 在肿瘤进展的晚期形成，由高度进化和侵略性的克隆形成，这些克隆是多年来的赢家 在原发肿瘤中的选择？或者转移是否在肿瘤发展的早期就已经形成，通过 进化程度较低的肿瘤细胞？如果这两种情况都存在，这种“早期”转移的行为会不会与“晚期”的表现不同？ 扩散肿瘤细胞？方法。我们已经开发了一种方法来重建癌症的进化 非常准确地记录历史。我们的方法依赖于对超可变的插入/缺失突变的分析， 非编码聚鸟嘌呤重复序列。这些序列中编码的血统信息异常丰富： 在系统发育重建方面，只需几十个重复序列的基因分型就可以胜过外显子组测序。 利用聚鸟嘌呤指纹图谱，我们最近发现，区域淋巴转移不是 大多数结直肠癌的肝转移来源，而不是广泛接受的范例。目标和影响。 在这里，我们建议建立在这些结果的基础上，并进一步阐明转移瘤演变中的关键事件。 结直肠癌。我们将确定肺部的致命性远处转移是否是从专门化转移演变而来的。 位于结肠淋巴结内的克隆。我们之前已经确定65%的肝转移瘤是 直接从原发肿瘤种植，但对胃肠道血管的解剖表明 对于其他远处转移，这一比例可能会显著降低。如果这一假设得到证实，我们的 对淋巴管在结直肠癌中的作用的认识将从根本上改变。第二，我们 目前的初步数据表明，其进化轨迹偏离 进展早期的原发肿瘤的侵袭性比出现转移的肿瘤小得多 后来的阶段。我们建议在一个大的患者队列中研究和证实这一现象。成功者 结果将是一种简单、经济有效的测试来预测转移性患者子集的长期生存 癌症。因为一些患者尽管患有转移性疾病，仍能存活数年甚至数十年，而另一些患者 在确诊后的几周内死亡，这种风险分层将对患者和他们的 照顾者。

Background. Metastasis to vital organs is the cause of death in a large majority of cancer patients. Although it is of eminent clinical importance to understand how systemic disease evolves, metastasis remains one of the least understood aspects of cancer progression. We still do not have the answers to many fundamental questions: Are metastasis founders a random selection of cells from primary tumors in which all cells have essentially equal metastatic ability? Or do specialized metastatic clones evolve, perhaps in intermediate sanctuary spaces like regional lymph nodes, and then proceed to colonize distant body parts? Are metastases formed late in tumor progression, by highly evolved and aggressive clones that are the winners of many years of selection within the primary tumor? Or can metastases already be formed early in tumor development, by less evolved tumor cells? If both scenarios exist, would such “early” metastases behave differently from “late” disseminating tumor cells? Method. We have developed a methodology to reconstruct a cancer's evolutionary history with great accuracy. Our method relies on the analysis of insertion/deletion mutations in hypermutable, non-coding polyguanine repeats. The lineage information encoded in these sequences is unusually rich: genotyping of only a few dozen repeats can outperform exome sequencing for phylogenetic reconstruction. Using polyguanine fingerprinting, we have recently shown that regional lymph node metastases are not the source of liver metastases in most colorectal cancers, in contrast to a widely held paradigm. Aims and Impact. Here, we propose to build upon these results and further elucidate critical events in the evolution of metastatic colorectal cancer. We will determine if lethal distant metastases in the lungs evolve from specialized metastatic clones that reside in the colonic lymph nodes. We have previously established that 65% of liver metastases are seeded directly from the primary tumor, but the anatomy of the gastrointestinal vasculature suggests that this percentage could be significantly lower for other distant metastases. If this hypothesis were confirmed, our understanding of the role of the lymphatics in colorectal cancer would be fundamentally altered. Second, we present preliminary data indicating that distant metastases whose evolutionary trajectory diverged from the primary tumor in early progression stages are considerably less aggressive than metastases that emerge in later stages. We propose to study and confirm this phenomenon in a large patient cohort. The successful outcome will be a simple, cost-effective test to predict long-term survival in a subset of patients with metastatic cancer. Since some patients can survive for years or even decades in spite of metastatic disease, while others die within weeks of diagnosis, such risk stratification would be of substantial benefit to both patients and their care providers.