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：
Pinkal Desai
金额：
$ 66.51万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
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：
https://reporter.nih.gov/project-details/10378484
关键词：
Acute Myelocytic Leukemia Age Age-Years Alleles Ascorbic Acid Blood Blood Banks Blood specimen Cells Chronic Lymphocytic Leukemia Clinical Clinical Trials Clonal Expansion Cohort Studies DNA Data Development Diagnosis Disease Epidemiology Future Genes Genomics Glucose Goals Health Care Costs Hematologic Neoplasms Hematology Hematopoiesis Individual Inflammation Inflammatory Intercept Intervention JAK2 gene Kinetics Large-Scale Sequencing Link Malignant Neoplasms Medicine Metabolic Metabolic Pathway Methods Molecular Monitor Morbidity - disease rate Multiple Myeloma Mutation Nature Obesity Outcome Participant Pattern Persons Plasma Positioning Attribute Precancerous Conditions Predictive Factor Prevalence Prevention Prevention strategy Prospective cohort Publishing Randomized Controlled Trials Reporting Research Risk Risk Assessment Risk Factors Sampling Shapes Somatic Mutation Specimen Spliceosomes TP53 gene Time United States Woman Women&apos s Health Work adjudicate base cancer diagnosis case control cell growth chemokine cohort deep sequencing follow-up founder mutation high risk improved inflammatory marker innovation insight leukemia/lymphoma metabolomics modifiable risk mortality multidisciplinary novel peripheral blood population based pre-clinical premalignant prevent preventive intervention prospective research study risk prediction statistics tumorigenesis

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.

抽象的克隆造血（CH）定义为在外周血中可检测到的获得性突变的存在没有血液恶性肿瘤（HM）的正常健康个体已通过测序得到了很好的表征基于人群的队列研究。CH 的存在与最终 HM 的风险增加 12 倍有关。需要数据来描述疾病特异性和突变特异性风险以及可能影响风险的因素我们在之前的工作中已经证明了 WHI 的参与者从 CH 到 HM 的进化轨迹。患有 AML 的人在发病前 9.6 年携带突变的可能性是其他人的四倍与具有 TP53、IDH1/2 和剪接体基因与 AML 风险增加高度相关，并且在对照中很少存在。长期目标是确定有助于 HM 发展的突变和细胞外在因素从而为未来HM拦截和预防的临床试验提供基础。代谢因素和炎症影响 CH 扩张的能力我们的中心假设是。可以前瞻性地预测预测 HM 发展的突变、炎症和代谢因素确定，从而能够改进风险评估，我们将利用在以下地点收集的外周血样本。基线来自女性健康倡议 (WHI) 队列，该队列前瞻性地跟踪了 168,808 名女性中位数为 10.8 年。所有癌症结果均由中央审查决定。确定以下内容：(1) 基线前 HM 突变和特定 HM 发展的风险我们将选择 400 例 HM 患者（200 例慢性淋巴细胞白血病 (CLL) 和 200 例）。多发性骨髓瘤病例）以及年龄匹配的 400 名在 WHI 随访期间未发生 HM 的对照 (2) 确定代谢和炎症异常对促进 CH 扩张和我们的研究很重要，因为没有已知的干预措施。预防或延缓 CH 进展为 HM 的策略，一般而言，前瞻性、随机、对照预防策略的试验需要多年的跟踪才能得出明确的结论。根据突变、炎症和代谢因素确定 HM 风险最高的个体，为监测 HM 风险最高的 CH 患者提供依据。为预防 HM 发生的干预策略提供新颖的见解。在研究影响疾病的突变、代谢以及炎症因素方面具有创新性使用来自大量女性的长期数据来评估 CH 到 HM 的进展。