PO.PS01.10 · 人群科学

儿童癌症幸存者中癌症治疗相关的心脏毒性：多种生物学年龄加速测量指标的比较与整合视角

Cancer treatment-related cardiotoxicity among survivors of childhood cancer: A comparative and integrated view of multiple measures of biological age acceleration

编号 867 展板 13 时间 4/19 02:00–05:00 区域 Section 34 主讲 Xiaoxi Meng, PhD

分会场 Survivorship Research

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作者与单位 Authors & Affiliations

Xiaoxi Meng¹, Tiffany Eulalio¹, Kwangyeon Oh¹, Noel-Marie Plonski¹, Kyla Shelton¹, Heather L. Mulder¹, John B. Easton¹, Jinghui Zhang¹, Emily Walker¹, Geoffrey A. Neale¹, Deo Kumar Srivastava¹, Rebecca M. Howell², Jeanne S. Mandelblatt³, Bonnie Ky⁴, Stephanie B. Dixon¹, Gregory T. Armstrong¹, Melissa Maria Hudson¹, Kirsten K. Ness¹, Zhaoming Wang¹

¹St. Jude Children's Research Hospital, Memphis, TN,²The University of Texas MD Anderson Cancer Center, Houston, TX,³Georgetown University, Washington, DC,⁴University of Pennsylvania, Philadelphia, PA

摘要 Abstract

中文摘要

引言：越来越多的证据表明，儿童癌症幸存者会经历生物学年龄加速（BioAgeAccel），并且心血管疾病风险增加。我们对多种BioAgeAccel测量指标进行了整合分析，以探讨衰老如何与治疗相关毒性及心血管风险相关，以及在不同方法学框架下开发的生物标志物如何捕捉这一通路。方法：心血管疾病（CVD）定义为心肌病或心肌梗死（MI）。使用Illumina EPIC BeadChips对2,941名圣裘德终生队列（St. Jude Lifetime Cohort）参与者的外周血单个核细胞DNA甲基化（DNAm）图谱进行检测。生物学年龄采用43种基于DNAm的生物标志物评估，包括GrimAge、PhenoAge和DunedinPACE等表观遗传时钟，以及C反应蛋白（DNAmCRP）等分子生物标志物。BioAgeAccel定义为在DNAm采血时将生物学年龄对实际年龄回归后所得的残差（DunedinPACE除外）。心脏毒性治疗暴露包括可能暴露心脏的放疗（heart-RT；平均剂量>15 Gy视为高剂量）和蒽环类化疗（累积剂量≥250 mg/m2多柔比星当量视为高剂量）。多变量logistic回归模型评估了各生物标志物与CVD的关联。BioAgeAccel还被作为heart-RT或蒽环类暴露与CVD之间的中介进行评估，以探讨其在因果通路中的作用。中介分析针对每个生物标志物单独进行，并针对由主成分分析得出的综合测量指标进行。结果：癌症确诊时的中位年龄为6.1岁（范围0-23.6；Q1-Q3：2.8-12.6），DNAm采血时的中位年龄为30.1岁（范围0.2-66.6；Q1-Q3：21.7-38.0）。总体而言，9.4%发生心肌病（中位发病年龄34.7岁），2.3%发生MI（中位发病年龄40.7岁）。大多数BioAgeAccel测量指标在高剂量heart-RT后升高，与高剂量蒽环类的关联较少。GrimAge的PC版本与MI的关联最强（OR=1.85，95%CI：1.45-2.36；Bonferroni P=4.06E-05），DNAmCRP与心肌病的关联最强（OR=1.31，95%CI：1.14-1.50；Bonferroni P=5.17E-03）。中介估计值在各生物标志物间有所不同。一项综合BioAgeAccel测量指标解释了heart-RT与MI关联的31.6%、heart-RT与心肌病关联的35.9%以及蒽环类与心肌病关联的7.7%。结论：BioAgeAccel测量指标在与心脏毒性及治疗相关衰老通路的关联上各不相同。这些发现支持进一步完善和验证基于DNAm的衰老生物标志物，以推进未来对幸存者长期CVD的风险分层和靶向预防。

查看英文原文 English abstract

Introduction: Mounting evidence suggests that childhood cancer survivors experience biological age acceleration (BioAgeAccel) and are at increased risk for cardiovascular disease. We performed an integrated analysis of multiple BioAgeAccel measures to examine how aging relates to treatment-related toxicity and cardiovascular risk, and how biomarkers developed under different methodological schemes capture this pathway. Methods: Cardiovascular disease (CVD) was defined as either cardiomyopathy or myocardial infarction (MI). DNA methylation (DNAm) profiles of peripheral-blood-mononuclear-cells from 2,941 St. Jude Lifetime Cohort participants were generated using Illumina EPIC BeadChips. Biological age was assessed using 43 DNAm-based biomarkers, including epigenetic clocks such as GrimAge, PhenoAge, and DunedinPACE, as well as molecular biomarkers such as C-reactive protein (DNAmCRP). BioAgeAccel was defined as residuals from regressing biological age on chronological age at DNAm blood draw (except DunedinPACE). Cardiotoxic treatment exposures included radiation potentially exposing the heart (heart-RT; mean dose >15 Gy considered high-dose) and anthracycline chemotherapy (cumulative dose ≥250 mg/m 2 doxorubicin equivalents considered high-dose). Multivariable logistic regression models evaluated the associations of each biomarker with CVD. BioAgeAccel was also evaluated as a mediator between heart-RT or anthracycline exposure and CVD to examine its role in the causal pathway. Mediation analyses were conducted for each biomarker individually and for a composite measure derived from principal component analysis. Results: Median age at cancer diagnosis was 6.1 years (range 0-23.6; Q1-Q3: 2.8-12.6), and at DNAm blood draw was 30.1 years (range 0.2-66.6; Q1-Q3: 21.7-38.0). Overall, 9.4% developed cardiomyopathy (median onset 34.7 years), and 2.3% developed MI (median onset 40.7 years). Most BioAgeAccel measures were elevated after high-dose heart-RT, with fewer associations for high-dose anthracyclines. PC version of GrimAge showed the strongest association with MI (OR=1.85, 95%CI: 1.45-2.36; Bonferroni P =4.06E-05), and DNAmCRP showed the strongest association with cardiomyopathy (OR=1.31, 95%CI: 1.14-1.50; Bonferroni P =5.17E-03). Mediation estimates varied across biomarkers. A composite BioAgeAccel measure accounted for 31.6% of the heart-RT-MI association, 35.9% of the heart-RT-cardiomyopathy association, and 7.7% of the anthracycline-cardiomyopathy association. Conclusions: BioAgeAccel measures vary in their associations with cardiotoxicities and treatment-related aging pathways. These findings support further refinement and validation of DNAm-based aging biomarkers to advance future risk stratification and targeted prevention of long-term CVD in survivors.

利益披露 Disclosure

X. Meng, None.. K. Oh, None.. K. Shelton, None.. H. L. Mulder, None.. J. B. Easton, None.. J. Zhang, None.. E. Walker, None.. R. M. Howell, None.. J. S. Mandelblatt, None.. B. Ky, None.. S. Dixon, None.

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