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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

基本信息

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
项目类别：
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

项目摘要

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。转移到重要器官是绝大多数癌症患者死亡的原因。尽管它