Long-term survivors of childhood cancer (LTS) have greater than an 8-fold increased risk of CV mortality compared to a healthy population 25 years after therapy. This risk increases progressively over time and appears related in part to anthracycline chemotherapy. Since 1:570 young adults in the US aged 20-45 by 2010 is projected to be a childhood cancer survivor and half will have had anthracycline therapy, the mechanism of this toxicity to prevent or treat it becomes critical to understand. Genetics (either natural genotypes or induced changes) may play a role in the susceptibility of anthracycline toxicity for each individual. In animal models of anthracycline cardiotoxicity, irreversible mitochondrial impairment, in part related to free-radical injury during therapy, leading to late cardiomyopathy is found but this has not been studied in humans. Mutations of the genes know to cause hemochromatosis (HFE mutations) may also lead to susceptibility to toxicity. In this application, Aim 1 will be to determine the frequency of mitochondrial DNA (mtDNA) mutations in pediatric acute lymphoblastic leukemia (ALL) survivors enrolled in the Dana Farber Cancer Institute Consortium. We will also determine if there are differences in mutation rates between children who received the cardioprotectant, dexrazoxane, versus those who did not. We will correlate the degree of mutations to other markers of cardiac function (echocardiographic measures and serum biomarkers of cardiac risk).
Aim 2 will determine if HFE mutations are associated with greater long-term cardiotoxicity as measured by echocardiography and serum biomarkers. We will enroll a total of 200 ALL survivors enrolled in the DFCI ALL consortium who were enrolled in studies 91-001, 95-001, and 00-001. Only 50% will have received the cardioprotectant, dexrazoxane. mtDNA and HFE studies will be obtained >4 years from diagnosis with simultaneous evaluation of cardiac function via echocardiography and analysis of serum biomarkers of cardiac risk (lipids, proBNP, hsCRP, cTnT). We will determine: 1. If there is a higher frequency of mtDNA mutations associated with prior anthracycline treatment and if dexrazoxane is protective against these mutations 2. If mtDNA mutation relate to increased CV risk of cardiomyopathy, premature atherosclerosis; 3. If the HFE mutations are related to increased cardiotoxicity of anthracyclines. This study will elucidate the molecular mechanisms of anthracycline cardiotoxicity in pediatric ALL cancer survivors. ? ? ? ?
| Bansal, Neha; Barach, Paul; Amdani, Shahnawaz M et al. (2018) When is early septal myectomy in children with hypertrophic cardiomyopathy justified? Transl Pediatr 7:362-366 |
| Lipshultz, Steven E (2018) Letter by Lipshultz Regarding Article, ""Anthracycline Cardiotoxicity: Worrisome Enough to Have You Quaking?"" Circ Res 122:e62-e63 |
| Adams, Michael Jacob; Fisher, Susan G; Lipshultz, Steven E et al. (2018) Risk of Coronary Events 55 Years after Thymic Irradiation in the Hempelmann Cohort. Cardiooncology 4: |
| Temple, Jennifer L; Bernard, Christophe; Lipshultz, Steven E et al. (2017) The Safety of Ingested Caffeine: A Comprehensive Review. Front Psychiatry 8:80 |
| Hutchins, Kelley K; Siddeek, Hani; Franco, Vivian I et al. (2017) Prevention of cardiotoxicity among survivors of childhood cancer. Br J Clin Pharmacol 83:455-465 |
| Lipshultz, Steven E; Anderson, Lynn M; Miller, Tracie L et al. (2016) Impaired mitochondrial function is abrogated by dexrazoxane in doxorubicin-treated childhood acute lymphoblastic leukemia survivors. Cancer 122:946-53 |
| Franco, Vivian I; Lipshultz, Steven E (2015) Cardiac complications in childhood cancer survivors treated with anthracyclines. Cardiol Young 25 Suppl 2:107-16 |
| Lipshultz, Steven E; Franco, Vivian I; Miller, Tracie L et al. (2015) Cardiovascular disease in adult survivors of childhood cancer. Annu Rev Med 66:161-76 |
| Lipshultz, Steven E; Chandar, Jayanthi J; Rusconi, Paolo G et al. (2014) Issues in solid-organ transplantation in children: translational research from bench to bedside. Clinics (Sao Paulo) 69 Suppl 1:55-72 |
| Lipshultz, Steven E; Cochran, Thomas R; Franco, Vivian I et al. (2013) Treatment-related cardiotoxicity in survivors of childhood cancer. Nat Rev Clin Oncol 10:697-710 |
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