Mentored Clinical Scientist Research Career Development Award (Parent K08)
指导临床科学家研究职业发展奖(家长K08)
基本信息
- 批准号:9647288
- 负责人:
- 金额:$ 24.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-01 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:ATM Gene MutationAftercareAgeAllelesBRCA1 geneBRCA2 geneBiological AssayBiological FactorsBloodBlood CellsBone MarrowCD34 geneCHEK2 geneCardiovascular DiseasesCellsCessation of lifeChromosomal InstabilityChromosome BreakageCitiesClinicalClonal EvolutionClone CellsCommunitiesCounselingCytotoxic ChemotherapyDNA DamageDNA Double Strand BreakDNA RepairDNA Sequence AlterationDNA sequencingDataDatabasesDefectDevelopmentDiseaseElectronic Health RecordEngraftmentEuropeanEvolutionExposure toFoundationsFrequenciesGeneral PopulationGenesGenetic screening methodGenomic InstabilityGerm-Line MutationGoalsHeart DiseasesHematologic NeoplasmsHematological DiseaseHematopoiesisHematopoieticHematopoietic stem cellsHereditary Breast CarcinomaHereditary Malignant NeoplasmHumanImmuneIndividualK-Series Research Career ProgramsKnowledgeLinkMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of pancreasMeasuresMedicalMentorsMolecular CloningMosaicismMusMutationParentsPatientsPhosphotransferasesPopulationPopulation StudyPredisposing FactorPredispositionPrevalenceProspective cohortRadiationRecommendationRelapseResearchRiskRisk AssessmentSamplingScientistTP53 geneTestingTimeTransplantationTreatment-Related CancerTumor BurdenVariantWomanalpha-Thalassemiabasebone cellcancer genomicscardiovascular disorder riskchemotherapyclinical predictorsclinically significantcytotoxicerythritol anhydrideexome sequencingexperimental studygenetic variantleukemiamalignant breast neoplasmmortalitymouse modelmutation carrierneoplasm registrynext generationnovelpatient populationprecision medicinepreventprospectiveresponseself-renewalsurvivorshiptumor
项目摘要
PROJECT SUMMARY
Genetic testing has made it possible to identify individuals with germline predisposition to cancer, e.g., carriers
of ATM, BRCA1, TP53 mutations. In addition to an increased risk of developing primary cancer, germline
mutation carriers may develop post-treatment-related malignancies (i.e., therapy-related leukemias), which
develop as new primary malignancies, rather than as relapse of the original tumors. I have recently shown that
germline mutation carriers may be at an increased risk of clonal hematopoiesis of indeterminate potential (CHIP).
CHIP is defined as somatic expanded blood cell clones in individuals without other hematologic disease. CHIP
is identified by gene variants found on next-generation DNA sequencing assays that are present at very low
frequency. These variants do not represent the germline, hematologic malignancy, post-zygotic mosaicism, or
circulating tumor burden. CHIP rates in healthy populations have been estimated to be 2% in those under the
age of 60, and increase with age and/or exposure to chemotherapy. The clinical significance of CHIP lies in the
increased risks for cardiovascular disease, primary and secondary leukemias, other hematologic malignancies,
and in general for all-cause mortality. I have recently gained data supporting the notion that ATM mutations
represent a novel germline predisposing factor to CHIP. In fact, I have shown that heterozygous ATM germline
mutation carriers: 1) are relatively frequent in the general population of healthy individuals (1 in 263 individuals
of European ancestry) and women with familial breast cancer (1.5 in 100 individuals); 2) have an apparent
increased rate of CHIP as compared to non-ATM mutation carriers; and 3) may have unique molecular CHIP
signatures. Therefore, ATM germline mutations are common and may predispose to CHIP. ATM regulates the
DNA damage response to double-strand DNA breaks through its kinase activity. Due to ATM haplo-insufficiency
and DNA-repair defect predisposition, I postulate that ATM germline mutation carriers may not have the proper
mechanisms of DNA repair and therefore cannot prevent CHIP, particularly after cytotoxic therapy
(chemotherapy or radiation). Guided by my preliminary data, I will test the hypothesis that ATM germline
mutations are associated with and predispose hematopoietic cells to develop CHIP. I will test my hypothesis
through the following Specific Aims: 1) to identify the clinical and biologic factors associated with ATM germline
mutations and CHIP and lay the foundation for prospective population-based studies, 2) to explore chromosomal
instability and dynamics of CHIP in a prospective cohort of ATM germline mutation carriers, and 3) determine if
CHIP can be recapitulated in a mouse model and predict clinical malignant evolution in ATM mutation carriers.
In summary, CHIP may pose a notable risk for ATM mutation carriers and determination of how it arises and
what drives its progression is necessary to counsel, screen and manage this patient population appropriately.
项目总结
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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