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

背景转移到重要器官是大多数癌症患者的死亡原因。虽然 对于了解全身性疾病如何演变具有突出的临床重要性，转移仍然是其中之一。 最不了解的癌症进展方面。我们仍然没有解决许多基本问题， 问题：转移建立者是从原发肿瘤中随机选择的细胞吗？ 转移能力基本相同吗或者是特化的转移克隆进化， 像局部淋巴结这样的避难所空间，然后继续在远处的身体部位定居？是转移 在肿瘤进展的后期，由高度进化和侵略性的克隆形成，这些克隆是多年的赢家。 在原发肿瘤中的选择性？或者转移灶在肿瘤发展的早期就已经形成， 进化较少的肿瘤细胞如果这两种情况都存在，那么这种“早期”转移的表现与“晚期”转移的表现是否不同？ 扩散的肿瘤细胞法我们开发了一种方法来重建癌症的进化过程， 历史非常准确。我们的方法依赖于对超变， 非编码聚鸟嘌呤重复序列。这些序列中编码的谱系信息异常丰富： 仅几十个重复的基因分型可以优于用于系统发育重建的外显子组测序。 使用多鸟嘌呤指纹，我们最近表明，区域淋巴结转移不是肿瘤的特征。 在大多数结直肠癌中，肝转移的来源，与广泛持有的范式相反。目标和影响。 在这里，我们建议建立在这些结果的基础上，进一步阐明转移性肝癌演变中的关键事件。 结肠直肠癌我们将确定肺中的致死性远处转移是否是由特发性转移瘤演变而来的。 结肠淋巴结中的克隆。我们以前已经确定，65%的肝转移瘤是由 直接从原发肿瘤中接种，但胃肠道血管的解剖结构表明， 其他远处转移的百分比可能显著更低。如果这一假设得到证实， 对大肠癌中代谢物作用的理解将从根本上改变。二是 目前的初步数据表明，远端转移，其演变轨迹偏离了从 早期进展阶段的原发性肿瘤的侵袭性明显低于 后期阶段。我们建议在一个大型患者队列中研究并证实这种现象。成功 结果将是一个简单的，成本效益的测试，以预测长期生存的一个子集的患者转移 癌由于一些患者可以生存数年甚至数十年，尽管转移性疾病，而其他人， 在诊断后数周内死亡，这种风险分层对患者及其家属都有实质性益处。 护理提供者。

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.