Sequencing Familial Lung Cancer
家族性肺癌测序
基本信息
- 批准号:10548750
- 负责人:
- 金额:$ 64.21万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-01-22 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AffectBiologicalCRISPR/Cas technologyCancer EtiologyCancer FamilyCell LineCellular biologyCollectionDNA LibraryDataDevelopmentEnvironmental ExposureEpidermal Growth Factor ReceptorEtiologyFamilyFamily Cancer HistoryFamily StudyFamily history ofFamily memberFrequenciesGenerationsGenesGeneticGenotypeGoalsGrantIndividualInheritedJointsMalignant NeoplasmsMalignant neoplasm of lungModalityMutationPARK2 geneParticipantPathway interactionsPenetrancePhenotypePopulationPredispositionPreventionPrevention MeasuresRB1 geneRecording of previous eventsResearchResourcesRiskRisk FactorsRoleSamplingSampling StudiesSecond Degree RelativeSmokingSmoking BehaviorSmoking HistorySpecimenTCF3 geneTP53 geneTestingTobacco smoking behaviorToxic Environmental SubstancesUpdateVariantcancer riskdata resourceexome sequencinggenetic analysisgenetic epidemiologygenetic linkage analysisgenetic selectiongenetic variantgenome wide association studyhigh riskhigh risk populationindexinginsightmembermortalitynext generationnovelprobandrisk variantscreeningsmoking exposuretargeted sequencingtobacco smoke exposuretumorigenesis
项目摘要
Lung cancer (LC) is the leading cause of cancer mortality in the U.S. Although tobacco smoking and some
environmental exposures contribute substantially to lung cancer risk, family studies show an additional strong
contribution from genetic factors. The Genetic Epidemiology of Lung Cancer Consortium (GELCC) has been
collecting samples and data from individuals with a strong family history of LC for the last 20 years, and has
assembled a unique resource of specimens and data. We have cancer phenotypes, smoking exposure data
and biological specimens available on multiple relatives in over 150 highly aggregated LC families (high-risk
familial lung cancer families, HRFLC cases/families) as well as phenotype, genotype and smoking data on
over 800 additional lung cancer cases who have a family history of at least one first or second degree relative
with lung cancer but for whom biospecimens were not available from additional relatives (familial cases from
biospecimen limited families, FLC cases). The goal of this research application is to identify genetic
factors that confer a high risk for lung cancer and to perform research to characterize further the
mechanisms by which these factors influence lung cancer risk. Identifying genetic factors for lung cancer
provides insight into the specific causes and pathways underlying its development. In addition, if high-risk
individuals can be identified they will reap the greatest benefit from screening modalities.
We propose three aims. In aim 1 we will identify genetic factors conferring a high-risk of lung
cancer development.. In this aim, we will complete analyses of WES data from 33 HRFLC families
comprising 291 individuals along with 114 FLC cases and case/control analyses of 1084 lung cancer cases
compared with 919 controls. We will use these data along with linkage analysis to prioritize uncommon variants
that have a strong effect on lung cancer risk. In Aim 2 we will extend and validate findings to a broader
population. We will also collect additional samples from LC cases in HRLFC. We will sequence the most
strongly associated variants and genes from Aim 1 in additional affected and unaffected individuals in the
sequenced families and an additional set of FLC cases and frequency matched controls. This aim will allow us
to a) validate findings from aim 1 using a larger collection of cases with a family history of lung cancer and
controls and b) assess the impact on risk in families according to smoking behavior and genetic contributions.
In Aim 3 we will study the impact that variants found in aims 1 and 2 have on cellular biology. We will
study the effect that specific mutations have on cellular phenotypes identified in aims 1 and 2 using CRISPR
technology. We will begin by studying mutations in PARK2 that we recently identified in 5 HRLFC families and
in E2A we previously studied. The proposed research will bring new insights into the etiology of lung cancer.
肺癌 (LC) 是美国癌症死亡的主要原因。尽管吸烟和一些癌症
家庭研究表明,环境暴露对肺癌风险有很大影响
遗传因素的贡献。肺癌遗传流行病学联盟 (GELCC)
从过去 20 年有明显 LC 家族史的个体中收集样本和数据,并已
汇集了独特的样本和数据资源。我们有癌症表型、吸烟暴露数据
以及 150 多个高度聚集的 LC 家族(高风险
家族性肺癌家族、HRFLC 病例/家族)以及表型、基因型和吸烟数据
超过 800 例肺癌病例至少有一名一级或二级亲属有家族史
患有肺癌,但无法从其他亲属处获得其生物样本(家族病例来自
生物样本有限家庭,FLC 病例)。本研究应用的目标是识别遗传
导致肺癌高风险的因素,并进行研究以进一步表征
这些因素影响肺癌风险的机制。识别肺癌的遗传因素
深入了解其发展的具体原因和途径。另外,如果存在高风险
可以确定哪些人将从筛查方式中获得最大利益。
我们提出三个目标。在目标 1 中,我们将确定导致肺癌高风险的遗传因素
癌症发展..为了这个目标,我们将完成对 33 个 HRFLC 家族的 WES 数据的分析
包括 291 人以及 114 例 FLC 病例和 1084 例肺癌病例的病例/对照分析
与 919 对照相比。我们将使用这些数据以及连锁分析来优先考虑不常见的变异
对肺癌风险有很大影响。在目标 2 中,我们将把研究结果扩展到更广泛的领域并进行验证
人口。我们还将从 HRLFC 的 LC 案例中收集更多样本。我们将排序最多
在其他受影响和未受影响的个体中,与目标 1 密切相关的变异和基因
测序的家庭和一组额外的 FLC 病例和频率匹配对照。这个目标将使我们
a) 使用更多具有肺癌家族史的病例来验证目标 1 的结果,并且
b) 根据吸烟行为和遗传贡献评估对家庭风险的影响。
在目标 3 中,我们将研究目标 1 和 2 中发现的变异对细胞生物学的影响。我们将
使用 CRISPR 研究特定突变对目标 1 和 2 中确定的细胞表型的影响
技术。我们将首先研究最近在 5 个 HRLFC 家族中发现的 PARK2 突变,
在我们之前研究过的E2A中。拟议的研究将为肺癌的病因学带来新的见解。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Christopher I. Amos其他文献
Shared susceptibility variations in autoimmune diseases: a brief perspective on common issues
自身免疫性疾病的共同易感性变异:对常见问题的简要看法
- DOI:
10.1038/gene.2008.92 - 发表时间:
2009 - 期刊:
- 影响因子:5
- 作者:
M. Seldin;Christopher I. Amos - 通讯作者:
Christopher I. Amos
Estimating the power of linkage analysis in hereditary breast cancer.
估计连锁分析在遗传性乳腺癌中的功效。
- DOI:
- 发表时间:
1990 - 期刊:
- 影响因子:9.8
- 作者:
S. A. Narod;Christopher I. Amos - 通讯作者:
Christopher I. Amos
Hereditary medullary thyroid carcinoma: genetic annalysis of three related syndromes. Groupe d'Etude des Tumeurs a Calcitonine.
遗传性甲状腺髓样癌:三种相关综合征的遗传分析。
- DOI:
- 发表时间:
1989 - 期刊:
- 影响因子:0
- 作者:
Hagay Sobol;S. A. Narod;I. Schuffenecker;Christopher I. Amos;Ezekowitz Ra;Lenoir Gm - 通讯作者:
Lenoir Gm
Impact of anticoagulation on recurrent thrombosis and bleeding after hematopoietic cell transplantation
抗凝对造血细胞移植后复发血栓和出血的影响
- DOI:
- 发表时间:
2021 - 期刊:
- 影响因子:0
- 作者:
Kylee L. Martens;Christopher I. Amos;C. Hernandez;P. Kebriaei;W. D. da Costa;Ryan S Basom;Chris Davis;Madeline F. Kesten;M. Carrier;D. Garcia;Stephanie J. Lee;Ang Li - 通讯作者:
Ang Li
External validation of the HIGH‐2‐LOW model: A predictive score for venous thromboembolism after allogeneic transplant
HIGH-2-LOW 模型的外部验证:同种异体移植后静脉血栓栓塞的预测评分
- DOI:
- 发表时间:
2022 - 期刊:
- 影响因子:0
- 作者:
Ang Li;Kylee L. Martens;Daniel Nguyen;Ryan S Basom;G. Rondon;Shida Jin;E. Young;Christopher I. Amos;Stephanie J. Lee;Chris Davis;David A. Garcia;Richard Champlin;E. Shpall;P. Kebriaei;Cristhiam M Rojas Hernandez - 通讯作者:
Cristhiam M Rojas Hernandez
Christopher I. Amos的其他文献
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{{ truncateString('Christopher I. Amos', 18)}}的其他基金
International Consortium for the Genetics of Biliary Tract Cancers Cholangiocarcinoma Genome Wide Association Study
国际胆道癌遗传学联盟胆管癌全基因组关联研究
- 批准号:
10608848 - 财政年份:2023
- 资助金额:
$ 64.21万 - 项目类别:
Optimizing colorectal cancer prevention: a multi-disciplinary, population-based investigation of serrated polyps using risk prediction and modeling
优化结直肠癌预防:利用风险预测和建模对锯齿状息肉进行多学科、基于人群的调查
- 批准号:
10436886 - 财政年份:2020
- 资助金额:
$ 64.21万 - 项目类别:
Optimizing colorectal cancer prevention: a multi-disciplinary, population-based investigation of serrated polyps using risk prediction and modeling
优化结直肠癌预防:利用风险预测和建模对锯齿状息肉进行多学科、基于人群的调查
- 批准号:
9916850 - 财政年份:2020
- 资助金额:
$ 64.21万 - 项目类别:
Optimizing colorectal cancer prevention: a multi-disciplinary, population-based investigation of serrated polyps using risk prediction and modeling
优化结直肠癌预防:利用风险预测和建模对锯齿状息肉进行多学科、基于人群的调查
- 批准号:
10650289 - 财政年份:2020
- 资助金额:
$ 64.21万 - 项目类别:
Optimizing colorectal cancer prevention: a multi-disciplinary, population-based investigation of serrated polyps using risk prediction and modeling
优化结直肠癌预防:利用风险预测和建模对锯齿状息肉进行多学科、基于人群的调查
- 批准号:
10207552 - 财政年份:2020
- 资助金额:
$ 64.21万 - 项目类别:
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