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.

项目总结/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， 很少有关于癌症基因组差异的研究，这需要生殖系、体细胞和临床数据， 同样的病人。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 战略布局Carrot-Zhang博士和其他人评估了遗传祖先对10，678名 来自癌症基因组图谱的33种癌症类型的患者，并强调了新的祖先特异性 从泛癌症和组织特异性分析的演变轨迹。我们还提出祖先 相关性具有深刻的组织特异性，因此，需要更多来自不同祖先的样本 用于组织特异性分析。在这种程度上，该提议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 药我们的总体目标是了解众所周知的，但神秘的，特定人群的基因组 肺腺癌的差异。我们的第一个目标是系统地描述祖先的景观 影响肺腺癌的基因组特征，因为我们有足够的能力检测新的关联。然后 在第二个目标中，胡萝卜-张博士将开发一种利用当地祖先的新统计方法 （基因组区域的祖先），以推断祖先相关的遗传力。 躯体特征我们还将探讨潜在的基因组差异相关的机制， 祖先我们的第三个目的是阐明血统对临床结果的影响，以提高 为少数民族人口提供精确的医疗服务。 博士Carrot-Zhang的长期职业目标是改善癌症预防，早期发现和治疗， 整合计算生物学、生殖系遗传学和体细胞基因组学方法， 癌症发生和发展的潜在机制。K99奖将进一步为她成功的 独立的研究生涯。胡萝卜-张博士的培训将在非凡的指导下进行 Matthew Meyerson博士（癌症基因组学）和亚历山大博士（萨沙）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）和大卫·夸特科夫斯基（临床肿瘤学）。拟议的研究计划 丹娜-法伯癌症研究所和布罗德癌症研究所的杰出机构环境将促进 院与Foundation Medicine的科学合作将为癌症提供卓越的资源 基因组学和祖先相关分析。建议的专业发展计划将提高胡萝卜博士- 张先生在实验室管理、基金撰写和领导方面的职业发展。