Applying Molecular Phylogeny to Predict Clinical Outcomes in Cancer

应用分子系统学预测癌症的临床结果

• 批准号: 7942536
• 负责人: KIMBERLY D SIEGMUND
• 金额: $ 24.66万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7942536
• 关键词: Age; Aging; Breast; Cancer Patient; Cell Line; Cell division; Cells; Characteristics; Clinical; Clonal Expansion; Colon Carcinoma; Colorectal Cancer; Development; Disease-Free Survival; Genomics; Goals; Lung; Malignant Neoplasms; Measures; Molecular; Mutation; Neoplasm Metastasis; Older Population; Outcome; Pathway interactions; Patients; Phylogeny; Population; Population Genetics; Prostate; Recording of previous events; Resistance; Solid Neoplasm; Somatic Cell; Staging; Testing; Time; anticancer research; cancer site; cell transformation; chemotherapy; high throughput technology; molecular marker; new technology; novel; public health relevance; tool; tumor

DESCRIPTION (provided by applicant): Our goal is to investigate the utility of cancer molecular phylogeny, a novel technological concept, to predict clinical outcomes. Rather than use novel high-throughput technologies to identify a molecular marker or signature to predict survival, we propose to use a molecular measure of cancer age. Estimation of cancer age is complicated by the fact that we do not observe the initial transformation and clonal expansion. What we do observe is a population of cells that are descendants of the original transformed cell. What we can measure is the molecular diversity of the population. Population genetics dictates that cells from an older population will show more diversity than cells from a younger population. Thus a molecular measure of tumor diversity should capture tumor age. We propose that tumor age will help predict patient outcomes. Thus, we challenge the current paradigm of finding a common pathway of cancer development that leads to poor survival. Instead we propose that older tumors are more diverse, regardless of the sequence of mutations accumulated, and that it is this diversity that makes them resistant to chemotherapy and prone to dissemination, thus leading to poorer outcomes. We propose to calibrate this novel technology using cell lines, in order to characterize the association between diversity and number of passages of cell division at a large number of (epi)genomic regions. We hypothesize that this basic, but presently unstudied, tumor characteristic of aging, will predict clinical outcome. We propose to demonstrate this for the special case of cancer patients with Stage III colon cancers. If successful, the approach has promise for predicting clinical outcome for solid tumors of many different cancer sites (e.g. breast, lung, prostate). This application has two Specific Aims: Aim 1: Characterize 70 somatic cell cancer molecular clocks to measure progression histories; Aim 2: Test whether the timing of metastases correlates with Stage III colorectal cancer disease-free survival. PUBLIC HEALTH RELEVANCE: Our hypothesis is that older cancers are more diverse cell populations and more resistant to treatment than younger cancers. However, this simple hypothesis has never been tested because we do not observe the initial transformation and clonal expansion of a cancer, and therefore cannot measure tumor age directly. We resolve this fundamental challenge by apply concepts from the field of population genetics to infer tumor age. In this project we apply tools for molecular phylogeny to predict clinical outcomes in cancer research.

描述（由申请人提供）：我们的目标是研究癌症分子系统发育这一新的技术概念在预测临床结果方面的应用。而不是使用新的高通量技术来识别分子标记或特征来预测生存，我们建议使用癌症年龄的分子测量。由于我们没有观察到初始转化和克隆扩增，癌症年龄的估计变得复杂。我们观察到的是一群细胞，它们是原始转化细胞的后代。我们能测量的是种群的分子多样性。群体遗传学表明，老年群体的细胞比年轻群体的细胞表现出更多的多样性。因此，肿瘤多样性的分子测量应该捕捉肿瘤的年龄。我们建议肿瘤年龄将有助于预测患者的预后。因此，我们挑战目前的范式，即寻找导致低生存率的癌症发展的共同途径。相反，我们提出，无论积累的突变序列如何，老年肿瘤更加多样化，正是这种多样性使它们对化疗产生抗药性，容易扩散，从而导致较差的结果。我们建议使用细胞系来校准这种新技术，以便在大量（epi）基因组区域中表征多样性与细胞分裂传代数之间的关系。我们假设这个基本的，但目前尚未研究的衰老肿瘤特征将预测临床结果。我们建议在III期结肠癌患者的特殊情况下证明这一点。如果成功，该方法有望预测许多不同癌症部位（如乳腺癌、肺癌、前列腺癌）实体瘤的临床结果。该应用程序有两个特定目的：目的1：表征70个体细胞癌分子钟以测量进展历史；目的2：测试转移时间是否与III期结直肠癌无病生存相关。