Pre-malignant mutation landscape and risk factors for progression to hematologic cancers
癌前突变情况和进展为血液癌的危险因素
基本信息
- 批准号:10378484
- 负责人:
- 金额:$ 66.51万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:Acute Myelocytic LeukemiaAgeAge-YearsAllelesAscorbic AcidBloodBlood BanksBlood specimenCellsChronic Lymphocytic LeukemiaClinicalClinical TrialsClonal ExpansionCohort StudiesDNADataDevelopmentDiagnosisDiseaseEpidemiologyFutureGenesGenomicsGlucoseGoalsHealth Care CostsHematologic NeoplasmsHematologyHematopoiesisIndividualInflammationInflammatoryInterceptInterventionJAK2 geneKineticsLarge-Scale SequencingLinkMalignant NeoplasmsMedicineMetabolicMetabolic PathwayMethodsMolecularMonitorMorbidity - disease rateMultiple MyelomaMutationNatureObesityOutcomeParticipantPatternPersonsPlasmaPositioning AttributePrecancerous ConditionsPredictive FactorPrevalencePreventionPrevention strategyProspective cohortPublishingRandomized Controlled TrialsReportingResearchRiskRisk AssessmentRisk FactorsSamplingShapesSomatic MutationSpecimenSpliceosomesTP53 geneTimeUnited StatesWomanWomen&aposs HealthWorkadjudicatebasecancer diagnosiscase controlcell growthchemokinecohortdeep sequencingfollow-upfounder mutationhigh riskimprovedinflammatory markerinnovationinsightleukemia/lymphomametabolomicsmodifiable riskmortalitymultidisciplinarynovelperipheral bloodpopulation basedpre-clinicalpremalignantpreventpreventive interventionprospectiveresearch studyrisk predictionstatisticstumorigenesis
项目摘要
ABSTRACT
Clonal hematopoesis (CH) defined as the presence of acquired mutations detectable in peripheral blood of
normal healthy individuals without hematologic malignancies (HM) has been well characterized by sequencing
population based cohort studies. The presence of CH is associated with >12-fold risk of eventual HMs. More
data are needed to delineate disease specific and mutation specific risk as well as factors that might shape the
evolutionary trajectory from CH to HM. We have demonstrated in our prior work that participants in the WHI
who developed AML were four times more likely to harbor a mutation a median of 9.6 years before the onset of
AML compared to controls (70% vs. 30%, OR 4.0, 95% C.I. 2.5-6.3) with mutations in TP53, IDH1/2, and
spliceosome genes being highly associated with increased risk of AML and rarely present among controls. The
long-term goal is to identify both mutational and cell-extrinsic factors that contribute to the development of HM
and thus provide the basis for future clinical trials of HM interception and prevention. Published data indicate
the ability of metabolic factors and inflammation to influence the expansion of CH. Our central hypothesis is
that mutational, inflammatory and metabolic factors that predict the development of HM can be prospectively
identified, thus enabling improved risk assessment. We will utilize peripheral blood samples collected at
baseline from the Women’s Health Initiative (WHI) cohort that prospectively followed 168,808 women for a
median of 10.8 years. All cancer outcomes were adjudicated by central review. Our specific aims will
determine the following: (1) the risk of baseline pre-HM mutations and development of specific HM among
participants in the WHI. We will select 400 cases of HM (200 chronic lymphocytic leukemia (CLL) and 200
cases of multiple myeloma) along with age matched 400 controls that did not develop HM during WHI follow up
(2) To determine the impact of metabolic and inflammatory abnormalities in promoting CH expansion and
impacting the progression from CH to HM. Our study is significant because there is no known intervention
strategy to prevent or delay the progression of CH to HM and in general, prospective, randomized, controlled
trials of prevention strategies require many years of follow-up to reach definitive conclusions. Our study will
establish individuals at highest risk of HM based on mutational, inflammatory and metabolic factors and
provide grounds for monitoring people individuals with CH at highest risk of HM. Moreover, these data will
provide novel insight into intervention strategies to prevent the onset of HM. The proposed research is
innovative in investigating mutational and metabolic as well as inflammatory factors that impact the
progression of CH to HM using long term data from a large cohort of women.
摘要
克隆性造血(CH)定义为外周血中可检测到的获得性突变的存在,
没有恶性血液病(HM)的正常健康个体已经通过测序得到了很好的表征
基于人群的队列研究。CH的存在与>12倍的最终HM风险相关。更
需要数据来描述疾病特异性和突变特异性风险,以及可能形成这些风险的因素。
从CH到HM的进化轨迹。我们在之前的工作中已经证明,WHI的参与者
发生AML的患者中,携带突变的可能性高出4倍,中位数为发病前9.6年。
AML与对照组相比(70% vs. 30%,OR 4.0,95% C.I. 2.5-6.3)具有TP 53、IDH 1/2和
剪接体基因与AML风险增加高度相关,在对照组中很少出现。的
长期的目标是确定突变和细胞外在因素,有助于HM的发展
从而为今后HM拦截和预防的临床试验提供依据。已发表的数据表明
代谢因素和炎症影响CH扩张的能力。我们的中心假设是
预测HM发展的突变、炎症和代谢因素可以前瞻性地
这有助于改进风险评估。我们将使用采集的外周血样本,
来自妇女健康倡议(WHI)队列的基线,该队列前瞻性地随访了168,808名妇女,
平均10.8岁。所有癌症结局均由中心审查裁定。我们的具体目标将
确定以下内容:(1)基线前HM突变和特定HM发生的风险,
参加WHI。我们将选择400例HM(慢性淋巴细胞白血病(CLL)200例,
多发性骨髓瘤病例)与400名年龄匹配的对照组(在WHI随访期间未发生HM)一起沿着
(2)确定代谢和炎症异常对促进CH扩张的影响,
影响从CH到HM的进展。我们的研究意义重大,因为没有已知的干预措施
预防或延迟CH进展为HM的策略,一般而言,前瞻性、随机、对照
预防战略的试验需要多年的后续行动才能得出明确的结论。我们的研究将
根据突变、炎症和代谢因素确定HM风险最高的个体,
为监测高危人群中的CH患者提供依据。此外,这些数据将
为预防HM的发生提供了新的干预策略。拟议的研究是
在研究突变和代谢以及炎症因素,影响
使用来自一个大的妇女队列的长期数据来评估CH向HM的进展。
项目成果
期刊论文数量(0)
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{{ truncateString('Pinkal Desai', 18)}}的其他基金
Pre-malignant mutation landscape and risk factors for progression to hematologic cancers
癌前突变情况和进展为血液癌的危险因素
- 批准号:
10596114 - 财政年份:2021
- 资助金额:
$ 66.51万 - 项目类别:
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