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
基本信息
- 批准号:10608848
- 负责人:
- 金额:$ 70.02万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-10 至 2028-03-31
- 项目状态:未结题
- 来源:
- 关键词:AfricaAfricanAmericanAsiaAsianAsian ancestryAsian populationBile duct carcinomaBiliary Tract CancerBiologicalCholangiocarcinomaCholelithiasisChromosome 6Chronic viral hepatitisClinicalCollaborationsCollectionComplexConsentCystDNADNA SequenceDataDevelopmentDiagnosisDiseaseEast AsianEnvironmental Risk FactorEpidemiologyEtiologyEuropeanExposure toFasciola hepaticaFrequenciesFutureGene TargetingGeneral PopulationGenesGeneticGenetic Predisposition to DiseaseGenetic VariationGenomic DNAGenotypeGoalsHaplotypesHeritabilityHispanic ancestryImmuneIndividualInflammatoryInheritedInstitutionInternationalMalignant NeoplasmsMediatingMethodsMethylene ChlorideModelingMolecularOccupational ExposureOpen Reading FramesOrganic solvent productOutcomePathologicPathway interactionsPatientsPhasePolymorphism AnalysisPopulationPredispositionPrevention strategyPrimary PreventionPrognosisProstate, Lung, Colorectal, and Ovarian Cancer Screening TrialPublishingRaceRadiology SpecialtyResearchRiskRisk FactorsSamplingSingle Nucleotide PolymorphismSpecimenSusceptibility GeneToxinVariantbile ductcancer preventioncancer riskcancer therapycancer typecohortdensityepidemiology studyexome sequencingexpectationfollow-upgenetic variantgenome wide association studygenome-widegenomic locusimprovedmulti-ethnicnovelprimary sclerosing cholangitisprospectiverare variantrecruitrepositoryscreeningsextargeted sequencingtargeted treatment
项目摘要
Abstract/Project Summary
Cholangiocarcinoma (CCA) is a highly lethal cancer that arises from the bile ducts and is often diagnosed at
an advanced stage with very poor prognosis. Factors associated with development of CCA include
inflammatory conditions of the bile ducts such as congenital cysts, gallstones, primary sclerosing cholangitis
(PSC), chronic hepatitis from viral and other causes, and occupational exposure to toxins such as the organic
solvents dichloromethane and 1,2-dichloropropane. In parts of Asia, liver fluke infestations of the bile ducts are
a major risk factor. However, the majority of patients who develop CCA worldwide have no known major risk
factor. Based on epidemiologic studies, it appears that CCA risk is due to a combination of genetic and
environmental factors. Genome-wide association studies (GWAS) have identified genetic susceptibility loci for
different cancer types, allowing development of risk models that can allow determination of an individual’s risk
of cancer. GWAS have also provided valuable information on the biological and molecular pathways that
contribute to risk of different cancers, allowing improved understanding of cancer development and progress in
cancer prevention and treatment. Because CCA is a relatively less common cancer, it has been difficult to study
large numbers of CCA patients and there have been no large CCA GWAS studies published, either for patients
with de novo CCA or for CCA developing in patients with PSC. Although PSC patients are up to 150 times
more likely to develop CCA than the general population, only 10-20% of PSC patients will progress to CCA.
Variation in the risk of CCA among PSC patients may be caused by a complex interplay between genetic and
environmental factors. Several studies indicate PSC has a strong genetic component; however, the impact of
genetic factors in PSC-related CCA development is yet to be elucidated. We hypothesize that different host
genetic variants are associated with CCA risk in de novo versus PSC-associated CCA cases. We have
developed a large multi-institutional and multi-national collaboration to identify gene variants associated with
CCA. The goal of this study is to use high-density single nucleotide polymorphism (SNP) analysis of genomic
DNA from CCA patients and controls. In a first phase of the study, we have genotyped DNA from 2829 CCA
patients, including 2412 of European and 417 of Asian descent. Of the European descent cases, 197 were
PSC-associated. Comparing the results with controls from the PLCO cohort, we identified a variant in the HLA
region on chromosome 6 that reached genome wide significance. A number of additional regions showed
suggestive results. We now propose an expansion of this discovery phase to acquire, genotype and sequence
DNA from an additional 7,267 CCA patients to confirm the validity of these suggestive results. We are also
expanding recruitment efforts to enrich the cohort in samples from non-European patients. We will use
sophisticated statistical genetic methods to analyze the results from the multi-ethnic cohort. Whole exome
sequencing will also be used to identify rare variants associated with CCA.
摘要/项目摘要
胆管癌(CCA)是一种高度致命的癌症,起源于胆管,通常在
晚期预后很差与CCA发展相关的因素包括
胆管炎性疾病,如先天性囊肿、胆结石、原发性硬化性胆管炎
(PSC)病毒性和其他原因引起的慢性肝炎,以及职业性接触毒素,如有机
溶剂二氯甲烷和1,2-二氯丙烷。在亚洲部分地区,肝吸虫感染的胆管是
一个主要的风险因素。然而,世界范围内发生CCA的大多数患者没有已知的主要风险
因子根据流行病学研究,CCA风险似乎是由于遗传和
环境因素全基因组关联研究(GWAS)已经确定了遗传易感性位点,
不同的癌症类型,允许开发风险模型,可以确定个人的风险
癌症。GWAS还提供了关于生物和分子途径的有价值的信息,
有助于不同癌症的风险,使人们更好地了解癌症的发展和进展,
癌症预防和治疗。由于CCA是一种相对不太常见的癌症,因此一直难以研究
大量的CCA患者,并且没有大型CCA GWAS研究发表,无论是患者
原发性CCA或PSC患者中发生CCA。虽然PSC患者高达150倍,
PSC患者比一般人群更容易发展为CCA,只有10-20%的PSC患者会发展为CCA。
PSC患者中CCA风险的变化可能是由遗传和基因之间复杂的相互作用引起的。
环境因素一些研究表明PSC具有很强的遗传成分;然而,
PSC相关CCA发展中的遗传因素尚待阐明。我们假设不同的宿主
与PSC相关CCA病例相比,遗传变异与新发CCA风险相关。我们有
开发了一个大型的多机构和多国合作,以确定与以下疾病相关的基因变异
CCA。本研究的目的是利用高密度单核苷酸多态性(SNP)分析基因组
来自CCA患者和对照的DNA。在研究的第一阶段,我们对来自2829个CCA的DNA进行了基因分型。
患者,包括2412名欧洲人和417名亚洲人后裔。在欧洲血统的病例中,
PSC相关。将结果与PLCO队列的对照组进行比较,我们确定了HLA中的一个变体,
6号染色体上的区域,达到全基因组意义。一些其他地区显示,
暗示性的结果。我们现在建议将这个发现阶段扩展到获取、基因分型和测序
来自另外7,267名CCA患者的DNA,以确认这些提示性结果的有效性。我们也
扩大招募工作,以丰富来自非欧洲患者的样本。我们将使用
复杂的统计遗传学方法来分析多种族队列的结果。全外显子组
测序也将用于鉴定与CCA相关的罕见变异。
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
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
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
Multi-ancestry GWAS meta-analyses of lung cancer reveal susceptibility loci and elucidate smoking-independent genetic risk
肺癌的多祖先全基因组关联研究荟萃分析揭示了易感位点并阐明了与吸烟无关的遗传风险
- DOI:
10.1038/s41467-024-52129-4 - 发表时间:
2024-10-04 - 期刊:
- 影响因子:15.700
- 作者:
Bryan R. Gorman;Sun-Gou Ji;Michael Francis;Anoop K. Sendamarai;Yunling Shi;Poornima Devineni;Uma Saxena;Elizabeth Partan;Andrea K. DeVito;Jinyoung Byun;Younghun Han;Xiangjun Xiao;Don D. Sin;Wim Timens;Jennifer Moser;Sumitra Muralidhar;Rachel Ramoni;Rayjean J. Hung;James D. McKay;Yohan Bossé;Ryan Sun;Christopher I. Amos;Saiju Pyarajan - 通讯作者:
Saiju Pyarajan
Uncovering shared genetic features between inflammatory bowel disease and systemic lupus erythematosus
- DOI:
10.1038/s41598-025-98991-0 - 发表时间:
2025-05-01 - 期刊:
- 影响因子:3.900
- 作者:
Vikram R. Shaw;Jinyoung Byun;Catherine Zhu;Rowland W. Pettit;Jeffrey M. Cohen;Younghun Han;Christopher I. Amos - 通讯作者:
Christopher I. Amos
Christopher I. Amos的其他文献
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{{ truncateString('Christopher I. Amos', 18)}}的其他基金
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:
$ 70.02万 - 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:
$ 70.02万 - 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:
$ 70.02万 - 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:
$ 70.02万 - 项目类别:
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