Understanding Ancestral Contribution to Lung Adenocarcinoma

了解祖先对肺腺癌的贡献

基本信息

批准号：
10667660
负责人：
Jian Zhang
金额：
$ 24.9万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10667660
关键词：
Address Admixture Advisory Committees African Argentina Asian ancestry Automobile Driving Award BRAF gene Brazil Cancer Biology Cancer Etiology Cancer Patient Career Mobility Carrots - dietary Cessation of life Clinical Clinical Data Clinical Oncology Collaborations Colombia Computational Biology Computing Methodologies Country DNA Sequence Alteration Dana-Farber Cancer Institute Data Data Set Development Development Plans Disparity ERBB2 gene Early Diagnosis Early treatment East Asian Environment Environmental Exposure Epidemiology Epidermal Growth Factor Receptor Ethnic Origin Etiology European Evolution Experimental Designs FBXW7 gene Foundations Frequencies Gene Mutation Genetic Genomic Segment Genomic approach Genomics Goals Grant Heritability Immune Immunotherapy Incidence Induced Mutation Institution Joints KRAS2 gene Laboratories Latin American Leadership Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of urinary bladder Medicine Mentorship Mexico Minority Groups Modernization Mutation Native American Ancestry Outcome Pathway interactions Patients Pattern Peru Population Population Genetics Prevention Process RAS genes Race Ras/Raf Receptor Protein-Tyrosine Kinases Reporting Research Sampling Statistical Methods The Cancer Genome Atlas Therapeutic Tissues Training United States Validation Variant Work Writing ancestry analysis cancer epidemiology cancer genome cancer genomics cancer health disparity cancer initiation cancer prevention cancer type career clinical sequencing cohort epidemiology study genomic locus improved innovation insight method development migration minority patient neoplasm resource never smoker novel novel marker precision medicine prognostic response small molecule inhibitor treatment response tumor tumor DNA tumor initiation tumor progression

项目摘要

PROJECT SUMMARY/ABSTRACT Although there are existing epidemiological studies of disparities in cancer incidence and outcomes, there are very few studies of disparities in cancer genomes, which requires both germline, somatic, and clinical data from the same patients. However, studying ancestry-specific genomic alterations is one of the most effective ways to understand the underpinning mechanisms in cancer disparity, and develop potential prevention and therapeutics strategies. Dr. Carrot-Zhang and others evaluated genetic ancestry effects on somatic alterations among 10,678 patients across 33 cancer types from The Cancer Genome Atlas, and highlighted novel ancestry-specific evolutionary trajectories from pan-cancer and tissue-specific analyses. We also suggested that ancestry associations were profoundly tissue specific, and therefore, more samples from diverse ancestries are required for tissue-specific analyses. To that extent, this proposal is based on large sequencing data sets composed of 1,153 lung cancer patients from Mexico and Colombia, and 60,085 lung cancer samples from Foundation Medicine. Our overall goal is to understand the well-known, but mysterious, population-specific genomic differences in lung adenocarcinoma. Our first aim is to systematically characterize the landscape of ancestry effects on genomic features of lung adenocarcinoma, as we are well powered to detect new associations. Then in the second aim, Dr. Carrot-Zhang will develop a novel statistical method leveraging the local ancestry (ancestry of a genomic region) from ancestry-admixed populations to infer the heritability of ancestry-associated somatic features. We will also explore the potential mechanisms underlying genomic differences related to ancestry. Our third aim is to elucidate the influence of ancestry on clinical outcome, in order to improve prognostics and precision medicine for the minority populations. Dr. Carrot-Zhang’s long-term career goal is to improve cancer prevention, early detection and treatment by integrating computational biology, germline genetics, and somatic genomics approaches to understand the mechanisms underlying cancer initiation and progression. The K99 award will further prepare her for a successful independent research career. Dr. Carrot-Zhang’s training will be carried out under the extraordinary mentorship of Dr. Matthew Meyerson (cancer genomics), and an advisory committee consisting of Drs. Alexander (Sasha) Gusev (population genetics and statistical genetics), Rameen Beroukhim (cancer biology), Heng Li (computational method development), and David Kwiatkowski (clinical oncology). The proposed research plan will be facilitated by the outstanding institutional environment of the Dana-Farber Cancer Institute and the Broad Institute. The scientific collaboration with Foundation Medicine will provide exceptional resources for cancer genomics and ancestry-related analyses. The proposed professional development plan will enhance Dr. Carrot- Zhang’s career advancement in laboratory management, grant-writing and leadership.

项目概要/摘要尽管现有的流行病学研究表明癌症发病率和结果存在差异，但关于癌症基因组差异的研究很少，这需要来自种系、体细胞和临床的数据然而，研究祖先特异性基因组改变是最有效的方法之一。了解癌症差异的基础机制，并开发潜在的预防和治疗方法 Carrot-Zhang 博士和其他人评估了遗传血统对 10,678 名体细胞改变的影响。癌症基因组图谱中 33 种癌症类型的患者，并强调了新的血统特异性来自泛癌和组织特异性分析的进化轨迹我们还提出了祖先。关联具有深刻的组织特异性，因此需要来自不同血统的更多样本就此而言，该提案基于由以下组成的大型测序数据集。来自墨西哥和哥伦比亚的 1,153 名肺癌患者，以及来自基金会的 60,085 份肺癌样本医学。我们的总体目标是了解众所周知但神秘的特定人群基因组。我们的首要目标是系统地描述肺腺癌的祖先特征。对肺腺癌基因组特征的影响，因为我们有能力检测新的关联。在第二个目标中，Carrot-Zhang 博士将利用当地血统开发一种新颖的统计方法（基因组区域的祖先）从祖先混合群体中推断祖先相关的遗传力我们还将探索与体细胞特征相关的基因组差异的潜在机制。我们的第三个目标是阐明血统对临床结果的影响，以改善临床结果。少数群体的预后和精准医学。 Carrot-Zhang 博士的长期职业目标是通过以下方式改善癌症预防、早期发现和治疗：计算整合生物学、种系遗传学和体细胞基因组学方法来理解 K99 奖将为她的成功做好进一步准备。 Carrot-Zhang博士的独立研究生涯将在非凡的指导下进行。 Matthew Meyerson 博士（癌症基因组学）和 Alexander 博士（Sasha）组成的咨询委员会 Gusev（群体遗传学和统计遗传学）、Rameen Beroukhim（癌症生物学）、Heng Li （计算方法开发）和 David Kwiatkowski（临床肿瘤学）。丹娜—法伯癌症研究所和博德癌症研究所的杰出机构环境将为您提供便利研究所与基金会医学的科学合作将为癌症提供特殊的资源。拟议的专业发展计划将增强胡萝卜博士的基因组学和血统相关分析。张在实验室管理、资助写作和领导力方面的职业发展。