Understanding Ancestral Contribution to Lung Adenocarcinoma

了解祖先对肺腺癌的贡献

• 批准号: 10190280
• 负责人: Jian Zhang
• 金额: $ 9.15万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2022-01-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190280
• 关键词: Address; Admixture; Advisory Committees; African; Argentina; Asians; 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; ERBB2 gene; Early Diagnosis; Early treatment; 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; Institutes; Joints; KRAS2 gene; Laboratories; Latin American; Leadership; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of urinary bladder; Medicine; Mentorship; Mexico; Minority; Minority Groups; Modernization; Mutation; Native American Ancestry; Outcome; Pathway interactions; Patients; Pattern; 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; base; 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; neoplasm resource; novel; novel marker; precision medicine; prognostic; response; small molecule inhibitor; tumor; tumor DNA; tumor initiation; tumor progression

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.

项目摘要/摘要 尽管现有关于癌症事件和结果差异的流行病学研究，但仍有 很少有关于癌症基因组差异的研究，该研究需要生殖，体细胞和临床数据 同一患者。但是，研究祖先特异性的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，并发展潜在的预防和治疗 策略。 Carrot-Zhang博士等人评估了遗传血统对10,678的体细胞改变的影响 来自癌症基因组图集的33种癌症类型的患者，并强调了新的祖先特异性 来自泛伴奏和组织特异性分析的进化轨迹。我们还建议祖先 相关是非常特定的，因此需要更多来自潜水祖先的样本 用于组织特异性分析。在某种程度上，该建议基于由大型测序数据集组成 来自墨西哥和哥伦比亚的1,153例肺癌患者，以及基金会的60,085例肺癌样本 药品。我们的总体目标是了解知名但神秘的，特定于人群的基因组 肺腺癌的差异。我们的第一个目的是系统地描述祖先的景观 由于我们有能力检测新关联，因此对肺腺癌的基因组特征的影响。然后 在第二个目标中，Carrot-Zhang博士将开发一种新型的统计方法，利用当地血统 （基因组区域的祖先）从祖先的群体种群来推断祖先相关的遗传力 躯体特征。我们还将探讨与 祖先。我们的第三个目标是阐明血统对临床结果的影响，以改善 少数群体的预后和精确医学。 Carrot-Zhang博士的长期职业目标是通过 整合计算生物学，种系遗传学和躯体基因组学方法来理解 癌症倡议和进展的机制。 K99奖将进一步为她的成功做好准备 独立研究职业。 Carrot-Zhang博士的培训将以非凡的心态进行 Matthew Meyerson博士（癌症基因组学）和一个由Drs组成的咨询委员会的成员。亚历山大（萨沙） Gusev（人口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）。拟议的研究计划 Dana-Farber癌症研究所和Broad的杰出机构环境将准备 研究所。与基金会医学的科学合作将为癌症提供出色的资源 基因组学和与祖先相关的分析。拟议的专业发展计划将增强Carrot博士 - 张在实验室管理，赠款写作和领导力方面的职业发展。