Hyaluronan Synthase 3 Variant and Anthracycline-Related Cardiomyopathy: A Report From the Children's Oncology Group

Wang, Xuexia; Liu, Wei; Sun, Can Lan; Armenian, Saro H.; Hákonarson, Hákon; Hageman, Lindsey; Ding, Yan; Landier, Wendy; Blanco, Javier G.; Chen, Lu; Quinõnes, Adolfo; Ferguson, Daniel; Winick, Naomi J.; Ginsberg, Jill P.; Keller, Frank G.; Neglia, Joseph P.; Desai, Sunil; Sklar, Charles A.; Castellino, Sharon M.; Cherrick, Irene; Dreyer, ZoAnn E.; Hudson, Melissa M.; Robison, Leslie L.; Yasui, Yutaka; Relling, Mary V.; Bhatia, Smita

doi:10.1200/jco.2013.50.3557

Cited by 132 publications

(110 citation statements)

References 37 publications

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“…Broader genomic studies, using a platform directed at cardiovascular variants, identified that HAS3 predisposed to cardiomyopathy, most strongly in those exposed to higher anthracycline doses. 89 These findings illustrate the principle that pharmacogenetic risk factors may be highly dependent on the exact therapeutic regimen, with some genetic risk factors most evident at lower drug doses and others most evident at higher drug doses.…”

Section: Anthracyclinesmentioning

confidence: 94%

Inherited genetic variation in childhood acute lymphoblastic leukemia

Moriyama

Relling

Yang

2015

Blood

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124

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Although somatically acquired genomic alterations have long been recognized as the hallmarks of acute lymphoblastic leukemia (ALL), the last decade has shown that inherited genetic variations (germline) are important determinants of interpatient variability in ALL susceptibility, drug response, and toxicities of ALL therapy. In particular, unbiased genome-wide association studies have identified germline variants strongly associated with the predisposition to ALL in children, providing novel insight into the mechanisms of leukemogenesis and evidence for complex interactions between inherited and acquired genetic variations in ALL. Similar genome-wide approaches have also discovered novel germline genetic risk factors that independently influence ALL prognosis and those that strongly modify host susceptibility to adverse effects of antileukemic agents (eg, vincristine, asparaginase, glucocorticoids). There are examples of germline genomic associations that warrant routine clinical use in the treatment of childhood ALL (eg, TPMT and mercaptopurine dosing), but most have not reached this level of actionability. Future studies are needed to integrate both somatic and germline variants to predict risk of relapse and host toxicities, with the eventual goal of implementing genetics-driven precision-medicine approaches in ALL treatment.

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Section: Anthracyclinesmentioning

confidence: 94%

Inherited genetic variation in childhood acute lymphoblastic leukemia

Moriyama

Relling

Yang

2015

Blood

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124

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“…To our knowledge we investigated all reported SNP associated with ACT. However, three papers were published after genotyping had been performed: (i) Lubieniecka et al reported in a small pilot study in leukemia patients an association between daunorubicin-induced cardiotoxicity and P450 oxidoreductase polymorphisms, (ii) Blanco et al reported a role of polymorphisms in carbonyl reductase genes in childhood cancer survivors [16,17], (iii) Wang et al recently published an association of Hyaluronan synthase 3 variant with ACT in 93 children receiving anthracyclines [34].…”

Section: Discussionmentioning

confidence: 98%

Clinical and genetic risk factors for epirubicin-induced cardiac toxicity in early breast cancer patients

Vulsteke

Pfeil

Maggen

et al. 2015

Breast Cancer Res Treat

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Anthracycline-induced cardiotoxicity (ACT) is a well-known serious adverse drug reaction leading to substantial morbidity. The purpose of this study was to assess ACT occurrence and clinical and genetic risk factors in early breast cancer patients. In 6 genes of interest (ABCC1, ABCC2, CYBA, NCF4, RAC2, SLC28A3), 10 single nucleotide polymorphisms (SNPs) involved in ACT were selected based on a literature search. Eight hundred and seventy-seven patients treated between 2000 and 2010 with 3-6 cycles of (neo) adjuvant 5-fluorouracil, epirubicin and cyclophosphamide (FEC) were genotyped for these SNPs using Sequenom MassARRAY. Main outcome measures were asymptomatic decrease of left ventricular ejection fraction (LVEF) > 10 % and cardiac failure grade 3-5 (CTCAE 4.0). To evaluate the impact of these 10 SNPs as well as clinical factors (age, relative dose intensity of epirubicin, left-sided radiotherapy, occurrence of febrile neutropenia, and planned and received cycles of epirubicin) on decrease of LVEF and cardiac failure, we performed uni- and multivariable logistic regression analysis. Additionally, exploratory analyses including 11 additional SNPs related to the metabolism of anthracyclines were performed. After a median follow-up of 3.62 years (range 0.40-9.60), a LVEF decline of > 10 % occurred in 153 patients (17.5 %) and cardiac failure in 16 patients (1.8 %). In multivariable analysis, six cycles of FEC compared to three cycles received and heterozygous carriers of the rs246221 T-allele in ABCC1 relative to homozygous carriers of the T-allele were significantly associated with LVEF decline of > 10 % (OR 1.3, 95 % CI 1.1-1.4, p < 0.001 and OR 1.6, 95 % CI 1.1-2.3, p = 0.02). Radiotherapy for left-sided breast cancer was associated with cardiac failure (OR 3.7, 95 % CI 1.2-11.5, p 0.026). The other 9 SNPs and clinical factors tested were not significantly associated. In our exploratory analysis, no other SNPs related to anthracycline metabolism were retained in the multivariate model for prediction of LVEF decline. ACT in breast cancer patients is related to number of received cycles of epirubicin and left-sided radiotherapy. Additional studies should be performed to independently confirm the potential association between rs246221 in ABCC1 and LVEF.

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“…Individual predisposition to anthracycline cardiotoxicity can also build on high expression levels of topoisomerase IIβ [60] or genetic variants of topoisomerase IIβ coregulating factors (retinoic acid receptor-γ) [61], polymorphisms of drug transporters that contribute to anthracycline distribution and elimination (ATP-binding cassette proteins of the multidrug resistance proteins family) [62], prooxidant enzymes (NADPH oxidase) [63], and matrix-remodeling enzymes (type 3 hyaluronan synthase) [64]. In brief, a constellation of factors may cause an unpredictable aggravation of cardiotoxicity.…”

Section: Primary Prevention Of Anthracycline Cardiotoxicitymentioning

confidence: 99%

Primary Prevention Strategies for Anthracycline Cardiotoxicity: A Brief Overview

Menna¹,

Salvatorelli

2017

Chemotherapy

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The clinical use of doxorubicin and other antitumor anthracyclines is limited by a dose-related risk of cardiomyopathy and heart failure which may occur “on treatment” or any time, from months to years, after completing chemotherapy. Dose reductions diminish the incidence of cardiac events attributable to anthracyclines, but heart failure still occurs in some patients exposed to low or moderate anthracycline doses. Because anthracyclines improve the life expectancy of patients with, for example, breast cancer or lymphomas, preventing or diminishing the risk of early or delayed cardiotoxicity is of obvious clinical importance. Here, we briefly review some potential strategies of primary prevention that are based on what we know about the molecular mechanisms of cardiotoxicity, and what can be done, or might be done, to interfere with the pharmacokinetic, pharmacodynamic, and genetic determinants of cardiotoxicity.

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Hyaluronan Synthase 3 Variant and Anthracycline-Related Cardiomyopathy: A Report From the Children's Oncology Group

Cited by 132 publications

References 37 publications

Inherited genetic variation in childhood acute lymphoblastic leukemia

Inherited genetic variation in childhood acute lymphoblastic leukemia

Clinical and genetic risk factors for epirubicin-induced cardiac toxicity in early breast cancer patients

Primary Prevention Strategies for Anthracycline Cardiotoxicity: A Brief Overview

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