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

阐明结直肠癌转移的进化史：基本原理和临床应用

• 批准号: 10515806
• 负责人: Kamila Naxerova
• 金额: $ 12.09万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10515806
• 关键词: Anatomy; Belief; Body part; Cancer Patient; Cause of Death; Cells; Circulation; Clinic; Clinical; Clonal Evolution; Collaborations; Colon; Colorectal Cancer; Data; Development; Diagnosis; Disease; Disseminated Malignant Neoplasm; Distant; Distant Metastasis; Event; Evolution; Extravasation; Fingerprint; Gastrointestinal tract structure; Genotype; Growth; Hospitals; Human; Investigation; Liver; Lung; Lymphatic; Lymphatic Metastasis; Lymphovascular; Malignant Neoplasms; Metastatic Neoplasm to Lymph Nodes; Metastatic Neoplasm to the Liver; Metastatic Neoplasm to the Lung; Methodology; Methods; Molecular; Neoplasm Metastasis; Organ; Outcome; Patients; Phylogenetic Analysis; Primary Neoplasm; Process; Random Allocation; Recording of previous events; Resected; Resolution; Role; Sampling; Site; Source; Specimen; Systemic disease; Testing; Time; Tissues; Travel; Untranslated RNA; Venous; anticancer research; cancer cell; capillary bed; care providers; clinically relevant; cohort; colorectal cancer metastasis; cost effective; draining lymph node; exome sequencing; gastrointestinal; genetic approach; improved; insertion/deletion mutation; insight; lymph nodes; metastatic colorectal; migration; neoplastic cell; novel; patient subsets; prevent; reconstruction; risk stratification; tumor; tumor progression

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.

背景。重要器官的转移是大多数癌症患者的死亡原因。虽然它 对于了解全身性疾病如何演变具有重要的临床意义，转移仍然是其中之一 癌症进展中最不为人所知的方面。我们仍然没有许多基本问题的答案 问题：转移创始人是否是从原发肿瘤中随机选择的细胞，其中所有细胞都具有 本质上相等的转移能力？或者是否会进化出专门的转移性克隆，也许是在中间阶段 区域淋巴结等避难所，然后继续殖民远处的身体部位？是否有转移 在肿瘤进展的晚期，由高度进化和侵略性的克隆形成，这些克隆是多年来的胜利者 原发肿瘤内的选择？或者在肿瘤发展的早期就已经形成转移，通过 进化程度较低的肿瘤细胞？如果两种情况都存在，这种“早期”转移的表现是否与“晚期”转移不同 传播肿瘤细胞？方法。我们开发了一种重建癌症进化的方法 历史非常准确。我们的方法依赖于对超可变插入/缺失突变的分析， 非编码多鸟嘌呤重复序列。这些序列中编码的谱系信息异常丰富： 在系统发育重建方面，仅几十个重复的基因分型就可以优于外显子组测序。 使用多鸟嘌呤指纹分析，我们最近表明区域淋巴结转移并不是 与广泛持有的范例相反，它是大多数结直肠癌肝转移的来源。目标和影响。 在这里，我们建议以这些结果为基础，进一步阐明转移性进化过程中的关键事件。 结直肠癌。我们将确定肺部致命的远处转移是否是由特殊的转移演变而来 驻留在结肠淋巴结中的克隆。我们之前已经确定 65% 的肝转移是 直接从原发肿瘤中播种，但胃肠道脉管系统的解剖结构表明，这 其他远处转移的百分比可能明显较低。如果这个假设得到证实，我们的 对淋巴管在结直肠癌中的作用的理解将从根本上改变。第二，我们 目前的初步数据表明，其进化轨迹偏离了远处转移 早期进展阶段的原发肿瘤的侵袭性远低于出现的转移肿瘤 后期阶段。我们建议在大型患者队列中研究并证实这一现象。成功者 结果将是一个简单的、具有成本效益的测试，可以预测一部分转移性患者的长期生存 癌症。尽管有些患者患有转移性疾病，但有些患者仍能存活数年甚至数十年，而另一些患者则可以存活数年甚至数十年。 如果患者在诊断后几周内死亡，这种风险分层对于患者及其家属都将大有裨益。 护理提供者。