Intra-tumor Heterogeneity in Colorectal Cancer Progression and Treatment Response

结直肠癌进展和治疗反应的肿瘤内异质性

基本信息

批准号：
9179073
负责人：
Karin Marie Hardiman
金额：
$ 17.5万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9179073
关键词：
Address Aftercare Algorithms Behavior Bioinformatics Biological Biopsy Biopsy Specimen Cancer Biology Cancer Etiology Cancer Patient Cessation of life Clinical Colorectal Cancer Copy Number Polymorphism Data Defect Development Disease Disease Progression Distant Metastasis Epigenetic Process Frequencies Future Genes Genetic Genetic Heterogeneity Geographic Locations Glioblastoma Goals Individual Knowledge Lesion Location Malignant Neoplasms Malignant neoplasm of lung Manuscripts Mentorship Metastatic Neoplasm to Lymph Nodes Minority Molecular Mutation Nature Neoplasm Metastasis Operative Surgical Procedures Pathway interactions Patients Phenotype Population Primary Lesion Primary Neoplasm Radiation Radiation therapy Recruitment Activity Rectal Cancer Renal Cell Carcinoma Research Personnel Resected Resistance Role Sampling Sequence Analysis Shapes Somatic Mutation Staging Techniques Testing Tissues Tumor Suppressor Genes United States Xenograft Model Xenograft procedure cancer genetics cancer therapy chemotherapy clinical phenotype colon cancer patients education planning gain of function mutation improved individual patient innovation loss of function lymph nodes malignant breast neoplasm multidisciplinary new therapeutic target novel therapeutic intervention prognostic value rectal response targeted treatment therapy resistant tissue resource tool translational study treatment response tumor tumor heterogeneity tumor progression

项目摘要

PROJECT SUMMARY: Colorectal cancer (CRC) remains the 3rd most common cause of cancer-related death in the United States. Treatment depends on location and stage and often includes radiation, chemotherapy and surgery. CRC phenotype and response to therapy vary significantly. CRCs arise in part due to the accumulation of somatic mutations and Copy Number Variants (CNV's). No particular change has been found that fully predicts phenotype. We and others have identified genetic sub-clones in CRC. In other tumor types, recent studies have highlighted the potential role of genetic heterogeneity in tumor phenotype, but in CRC the role of heterogeneity and tumor sub-clones in tumor progression and response to therapy remains unknown. Thus, we hypothesize the following: Substantial intra-tumoral genetic heterogeneity is common in primary CRCs, and the distinct sub-clones present in a primary lesion underpin CRC biological behavior and clinical phenotype. Distinct sub-clones in the primary lesion give rise to CRC lymph node (LN) and distant metastases. The sub- clones present in a CRC lesion vary in their response to chemotherapy and radiation therapy. Three specific aims are proposed to address the overarching hypotheses: Specific Aim 1: We will characterize the extent and nature of genetic sub-clones in CRCs by studying somatic genetic alterations in multiple, distinct geographic regions from each tumor used in aims 2 and 3. We will use bioinformatics tools to integrate mutations and CNV's to define genetic sub-clones within each tumor and compare sub-clones across tumors. Specific Aim 2: To compare sub-clones in primary CRC's to those in patient-matched LN metastases in 20 patients with the goal of defining the role of sub-clonal populations in metastatic progression. The questions we propose to answer are these: 1. Are the sub-clones that metastasize to the LNs from the majority or minority clones in the primary tumor? 2. Are individual LN metastasis made up of single or multiple sub-clones? 3. When there are multiple LN metastasis in an individual patient, are they derived from the same sub-clone from the primary tumor or multiple different sub-clones? Specific Aim 3A: To assess relationships between the sub-clones in the tumor and the response of rectal cancer patients to pre-operative chemotherapy and radiation, by analyzing 40 matched primary rectal cancers before and after treatment. We hypothesize that some rectal cancer sub- clones are sensitive and others resistant to chemo- and radiation therapy. Aim 3B: In parallel, we will create xenograft models of 20 of the rectal cancers and assess whether they mimic the response to standard chemotherapy and radiation seen in the matched patients. This proposal will utilize innovative sequencing and bioinformatics techniques along with patient samples and clinical information. Ultimately, greater understanding of the genetic mechanisms underlying CRC progression and response to treatment will allow novel, targeted therapies to be proposed and tested. This project, the multidisciplinary mentorship team, and educational plan will prepare the candidate to be a fully independent investigator in the field of colorectal cancer genetics.

项目概要：结直肠癌 (CRC) 仍然是美国癌症相关死亡的第三大常见原因。治疗取决于部位和分期，通常包括放疗、化疗和手术。 CRC 表型和对治疗的反应差异很大。 CRC 的出现部分是由于体细胞的积累突变和拷贝数变异（CNV）。没有发现任何特别的变化可以完全预测表型。我们和其他人已经鉴定出 CRC 的基因亚克隆。在其他肿瘤类型中，最近的研究强调了遗传异质性在肿瘤表型中的潜在作用，但在结直肠癌中异质性和肿瘤亚克隆在肿瘤进展和治疗反应中的作用仍然未知。因此，我们假设如下：原发性 CRC 中存在显着的瘤内遗传异质性，并且原发性病变中存在的不同亚克隆支撑着 CRC 的生物学行为和临床表型。原发病变中的不同亚克隆会产生 CRC 淋巴结 (LN) 和远处转移。子 CRC病变中存在的克隆对化疗和放疗的反应各不相同。三具体提出目标是为了解决总体假设：具体目标 1：我们将描述程度和通过研究多个不同地理区域的体细胞遗传改变，了解 CRC 中遗传亚克隆的性质目标 2 和 3 中使用的每个肿瘤的区域。我们将使用生物信息学工具来整合突变和 CNV 用于定义每个肿瘤内的遗传亚克隆并比较肿瘤之间的亚克隆。具体目标2：比较 20 名患有原发性 CRC 的患者中的亚克隆与患者匹配的淋巴结转移中的亚克隆确定亚克隆群体在转移进展中的作用的目标。我们提出的问题答案是： 1. 转移到 LN 的亚克隆是来自细胞内的大多数克隆还是少数克隆？原发肿瘤？ 2. 单个淋巴结转移是由单个还是多个亚克隆组成？ 3.当有单个患者体内有多处淋巴结转移，它们是否源自原发灶的同一亚克隆肿瘤还是多个不同的亚克隆？具体目标 3A：评估亚克隆之间的关系肿瘤和直肠癌患者对术前化疗和放疗的反应，通过分析 40 治疗前后匹配原发性直肠癌。我们假设某些直肠癌亚克隆对化疗和放射治疗敏感，而其他克隆则具有抗性。目标 3B：同时，我们将创建 20 种直肠癌的异种移植模型并评估它们是否模仿标准反应在匹配的患者中观察到化疗和放疗。该提案将利用创新的测序和生物信息学技术以及患者样本和临床信息。最终加深理解结直肠癌进展和治疗反应背后的遗传机制的研究将允许新的、有针对性的提出并测试的疗法。该项目、多学科导师团队和教育计划将使候选人成为结直肠癌遗传学领域完全独立的研究者。