Hereditary Genetics of Hepatocellular Carcinoma
肝细胞癌的遗传遗传学
基本信息
- 批准号:10366233
- 负责人:
- 金额:$ 17.79万
- 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:2022-02-01 至 2022-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAgeAge of OnsetAlcohol consumptionAlcoholsAnimal ModelBRCA2 geneCHEK2 geneCandidate Disease GeneChronicClinicalConfidence IntervalsDNA DamageDNA RepairDNA Repair GeneDefectDemographic FactorsDevelopmentDiagnosisEnrollmentEnvironmental Risk FactorExposure toFANCD2 proteinFamilyFamily Cancer HistoryFamily history ofFamily memberFanconi Anemia Complementation Group A ProteinFatty LiverFibrinogenFirst Degree RelativeGene ExpressionGenesGeneticGenetic ModelsGenetic Models for CancerGenetic studyHepatitis BHepatitis CHereditary Neoplastic SyndromesHistologicIndividualInheritedInstitutionInvestigationKnowledgeLinkLiver neoplasmsLoss of HeterozygosityMSH6 geneMalignant NeoplasmsMalignant neoplasm of liverMedical centerOdds RatioOutcomePMS2 genePathogenesisPathogenicityPatient CarePatientsPharmacotherapyPhenotypePilot ProjectsPlayPopulationPopulation ControlPractice GuidelinesPredispositionPrimary carcinoma of the liver cellsProteinsRecommendationRecording of previous eventsRiskRisk FactorsRoleStainsSusceptibility GeneTest ResultTestingToxic Environmental SubstancesTumor TissueVariantVirus Diseasesbasecancer cellcancer predispositioncancer riskcarcinogenesiscase controlclinical centerclinical practiceclinically relevantearly onsetexomefatty liver diseasegene functiongene panelgene repairgenetic associationgenetic panel testgenetic risk factorgenetic testinggenetic variantgenomic locushigh riskhomologous recombinationimprovedinhibitorinhibitor therapyinnovationliver cancer modelloss of functionmortalitypatient subsetspersonalized medicineprospectiverare variantrepairedresponsetargeted treatmenttreatment strategytumor
项目摘要
Project Summary
Hepatocellular Carcinoma (HCC) is a devastating and prevalent cancer of the liver with high rates of mortality.
Major risk factors include chronic viral infection (hepatitis B or C), fatty liver disease, alcohol use, and exposure
to environmental toxins. An independent risk factor is a family history of HCC, which raises the risk by more than
2.5-fold. However, despite evidence of familial risk, the inherited component remains unknown. It also remains
unexplored whether inherited gene variants play a pathogenic role in HCC development, or whether they could
be used to guide treatment with targeted therapies. We have pioneered an investigation into inherited (i.e.
germline) genetic factors associated with HCC. We have completed a pilot analysis of 217 patients with HCC
prospectively enrolled from our medical center for clinical-grade multigene panel genetic testing. We have
captured details about their personal and family cancer history, risk factors, and outcomes. In our pilot analysis,
we found a surprisingly high rate of pathogenic germline variants in cancer-associated genes in patients with
HCC, including numerous pathogenic and likely pathogenic variants in genes required for homologous repair,
DNA damage response (HR-DDR). We hypothesize that inherited loss-of-function variants in specific genes are
enriched in HCC, and that carriers can be treated with targeted therapies. In Aim 1, we will conduct genetic
association studies that are powered to detect clinically meaningful germline variants linked to HCC, and we will
examine predictors of hereditary cancer syndromes in HCC including age of onset and family history of cancer.
In Aim 2, we will explore the mechanism of HCC arising from defects in HR-DDR genes, and determine the
implications for targeted therapies. These innovative studies of the hereditary genetics of HCC have the potential
to personalize therapies for the subset of patients with hereditary cancer syndromes. We have assembled a
team of experts in HCC, hereditary genetics, and animal models to complete this investigation. This study has
the potential to impact on the care of patients with HCC in the US and worldwide.
项目摘要
肝细胞癌(HCC)是一种毁灭性的、普遍存在的肝脏癌症,死亡率很高。
主要的风险因素包括慢性病毒感染(乙型或丙型肝炎B)、脂肪肝、饮酒和暴露
环境毒素。一个独立的危险因素是肝细胞癌家族史,它使风险增加超过
2.5-fold.然而,尽管有家族风险的证据,遗传的成分仍然未知。委员会还
遗传性基因变异是否在HCC的发展中起致病作用,或者它们是否可以
用于指导靶向治疗。我们开创了一项关于遗传(即,
与HCC相关的生殖系)遗传因素。我们已经完成了对217例HCC患者的初步分析
从我们的医疗中心前瞻性招募临床级多基因面板基因检测。我们有
收集有关他们个人和家族癌症史、风险因素和结果的详细信息。在我们的试点分析中,
我们发现,在癌症相关基因中,
HCC,包括同源修复所需基因中的许多致病性和可能致病性变体,
DNA损伤反应(HR-DDR)。我们假设特定基因中的遗传性功能丧失变异是
在HCC中富集,并且载体可以用靶向疗法治疗。在目标1中,我们将进行遗传
关联研究,能够检测与HCC相关的有临床意义的生殖系变异,我们将
检查HCC中遗传性癌症综合征的预测因素,包括发病年龄和癌症家族史。
在目标2中,我们将探索由HR-DDR基因缺陷引起的HCC的机制,并确定HR-DDR基因缺陷对HCC的影响。
对靶向治疗的影响。这些关于肝癌遗传学的创新性研究有可能
为遗传性癌症综合征患者的子集提供个性化治疗。我们组建了一个
HCC、遗传学和动物模型方面的专家团队来完成这项研究。本研究
对美国和世界范围内HCC患者护理的潜在影响。
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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Kirk J Wangensteen其他文献
A method for lifelong genetic manipulation of regenerating hepatocytes in mouse
一种对小鼠再生肝细胞进行终身基因操作的方法
- DOI:
10.1038/cr.2008.121 - 发表时间:
2008-08-04 - 期刊:
- 影响因子:25.900
- 作者:
Kirk J Wangensteen;Andrew Wilber;Vincent W Keng;Yixin Chen;Ilze Matise;Laura Wangensteen;Clifford J Steer;R Scott McIvor;David A Largaespada;Xin Wang;Stephen C Ekker - 通讯作者:
Stephen C Ekker
Kirk J Wangensteen的其他文献
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