Admixture mapping of mosaic copy number alterations for identification of cancer drivers
用于识别癌症驱动因素的马赛克拷贝数改变的混合图谱
基本信息
- 批准号:10608931
- 负责人:
- 金额:$ 18.13万
- 依托单位:
- 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:2022-04-15 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdmixtureAfricanAfrican AmericanAfrican American populationAfrican ancestryAmericanBloodCell FractionCellsCessation of lifeClonal ExpansionComplementComputing MethodologiesDNA Sequence AlterationDataData SetDevelopmentDiseaseEarly DiagnosisEnsureEuropeanEuropean ancestryFrequenciesFundingGenesGeneticGenetic Population StudyGenetic VariationGenetic studyGenomic SegmentGenomicsGoalsGrantHaplotypesHematologic NeoplasmsHematologyHumanIncidenceIndividualInheritedJapaneseJapanese PopulationJointsK22 AwardLatinoLatino PopulationLinkLoss of HeterozygosityMalignant NeoplasmsMapsMentorsMethodologyMethodsMinority GroupsModelingMolecularMolecular ProfilingMosaicismMutationNon-MalignantNormal tissue morphologyOrganismPaintPathologicPatternPersonsPoint MutationPopulationPopulation GeneticsPreventionPrevention strategyPrognosisProliferatingPublicationsRecurrenceReportingResearchResearch PersonnelRisk AssessmentSamplingScreening for cancerSingle Nucleotide PolymorphismStatistical MethodsTestingTissuesTrainingTranslationsUnderrepresented PopulationsVariantWorkWritingadmixture mappingancestry analysiscancer biomarkerscancer genomicscancer preventioncancer riskcancer seedingcareerdetection methodfollow-upgenetic variantgenome sequencinggenome wide association studygenomic variationhigh riskimprovedinnovationinsightleukemiamethod developmentmosaicmosaic analysismosaic variantmulti-ethnicnovelpremalignantprogramsskillstranslational applicationstranslational potentialvariant detectionwhole genomezygote
项目摘要
PROJECT SUMMARY/ABSTRACT
Background: Somatic mosaicism arises due to the clonal expansion of a cell with an acquired mutation, which
leads to genetically distinct sub-populations of cells in an organism derived from a single zygote. As a clone
proliferates, its subclones can accumulate further molecular changes that seed cancer. A better understanding
of acquired point mutations and copy number changes in these clonal expansions can help elucidate the
earliest stages of cancer development. Studies of tissues from healthy individuals have found that those with
clonal mosaicism in blood, specifically copy number alterations (CNAs), have a ~10-fold higher risk of
developing hematological malignancies, thus underscoring the translational potential of mosaicism studies for
the development of improved risk assessment and cancer prevention strategies. Research up to now has
mainly focused on persons of European ancestry. My own preliminary results show differences in the genomic
landscape of CNAs between individuals of African American or Latino ancestry when compared with
Europeans. Understanding these differences and the underlying molecular mechanisms is critical in order to
include these still under-researched populations in translational mosaicism studies for early detection and
prevention of hematological and potentially other cancers. Proposed Research: Aim 1 is to address the great
need for comprehensive studies of mosaicism in American minority populations through a large-scale analyses
of CNAs in African American and Latino whole genome sequencing (WGS) data sets. This approach will
enable a robust comparison of mosaicism profiles across populations; WGS will allow for joint analysis of
CNAs and somatic point mutations to gain insights into mechanisms that underlie different rates and subtypes
of hematological malignancies across populations. Aim 2 is to develop novel methods to combine CNA and
haplotype level ancestry data for detection of variants associated with increased mosaicism rates. I will use
these methods to identify genetic variants that are associated with mosaicism and with increased cancer risk in
Latinos and African Americans. Candidate: I have led projects to discover and analyze acquired CNAs in
thousands of non-malignant tissues – first of their kind studies for pathologically normal and premalignant
tissues – as well as in cancer tissues that complement these. This expertise and my established track record in
the development of computational methods for human/cancer genomics, will ensure the successful completion
of these aims. As larger volumes of normal tissues are molecularly profiled, I will be able to extend methods
developed in Aim 2 to additional normal tissue types, and conduct integrative omics analyses. I will follow up
this work and the associated publications with an R01 proposal focused on translational applications of mosaic
mutations in normal tissues as markers for cancer risk assessment, early detection, and prognosis. The K22
award will be fundamental as I launch my independent investigator career, offering management and grant
writing training, helping to hone my skills as a mentor/PI and establish a long-term funded research program.
项目总结/摘要
背景:体细胞嵌合现象是由于具有获得性突变的细胞的克隆性扩增而产生的,
导致生物体中从单个受精卵衍生出遗传上不同的细胞亚群。为克隆
当细胞增殖时,它的亚克隆可以积累进一步的分子变化,从而产生癌症。更好地理解
获得性点突变和拷贝数的变化,这些克隆扩增可以帮助阐明
癌症发展的最早阶段。对健康个体组织的研究发现,
血液中的克隆镶嵌现象,特别是拷贝数改变(CNA),具有约10倍的高风险
发展血液恶性肿瘤,从而强调嵌合体研究的转化潜力,
制定更好的风险评估和癌症预防战略。到目前为止,
主要集中在欧洲血统的人。我自己的初步结果显示,
与非裔美国人或拉丁裔美国人相比,
欧洲人了解这些差异和潜在的分子机制至关重要,
将这些仍未充分研究的人群纳入翻译嵌合体研究中,以进行早期检测,
预防血液学和潜在的其他癌症。建议的研究:目标1是解决重大问题
需要通过大规模的分析,在美国少数民族人口的镶嵌综合研究
非裔美国人和拉丁美洲人全基因组测序(WGS)数据集的CNA。这种方法将
能够在人群中对镶嵌特征进行强有力的比较; WGS将允许联合分析
CNA和体细胞点突变,以深入了解不同比率和亚型的机制
血液恶性肿瘤的发病率。目的2是开发新的方法来结合联合收割机CNA和
用于检测与增加的嵌合率相关的变体的单倍型水平祖先数据。我会用
这些方法用于鉴定与嵌合现象和癌症风险增加相关的遗传变异,
拉丁裔和非洲裔美国人。候选人:我曾领导过一些项目,发现和分析获得的CNA,
数千种非恶性组织--首次对病理正常和癌前病变进行研究
组织-以及补充这些的癌组织。这种专业知识和我在这方面的良好记录
人类/癌症基因组学计算方法的发展,将确保成功完成
这些目标。随着大量的正常组织被分子分析,我将能够扩展方法
在目标2中开发的方法,用于额外的正常组织类型,并进行整合组学分析。我会跟进
这项工作和相关的出版物与R 01建议集中在翻译应用镶嵌
正常组织中的突变作为癌症风险评估、早期检测和预后的标志物。K22
在我开始我的独立调查员职业生涯时,该奖项将是至关重要的,它提供管理和资助
写作培训,帮助磨练我作为导师/PI的技能,并建立长期资助的研究计划。
项目成果
期刊论文数量(0)
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