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Candidate Gene Association Studies of Anthracycline-induced Cardiotoxicity: A Systematic Review and Meta-analysis.

ABSTRACT: Anthracyclines play an important role in the management of patients with cancer but the development of anthracycline-induced cardiotoxicity (ACT) remains a significant concern for most clinicians. Recently, genetic approach has been used to identify patients at increased risk of ACT. This systematic review assessed the association between genomic markers and ACT. A systematic literature search was performed in Medline, PubMed, Cochrane Central Register of Controlled Studies, CINAHL Plus, AMED, EMBASE and HuGE Navigator from inception until May 2016. Twenty-eight studies examining the association of genetic variants and ACT were identified. These studies examined 84 different genes and 147 single nucleotide polymorphisms. Meta-analyses showed 3 risk variants significantly increased the risk for ACT; namely ABCC2 rs8187710 (pooled odds ratio: 2.20; 95% CI: 1.36-3.54), CYBA rs4673 (1.55; 1.05-2.30) and RAC2 rs13058338 (1.79; 1.27-2.52). The current evidence remains unclear on the potential role of pharmacogenomic screening prior to anthracycline therapy. Further research is needed to improve the diagnostic and prognostic role in predicting ACT.

SUBMITTER: Leong SL

PROVIDER: S-EPMC5428315 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Candidate Gene Association Studies of Anthracycline-induced Cardiotoxicity: A Systematic Review and Meta-analysis.

Leong Siew Lian SL Chaiyakunapruk Nathorn N Lee Shaun Wen Huey SW

Scientific reports 20170227 1

Anthracyclines play an important role in the management of patients with cancer but the development of anthracycline-induced cardiotoxicity (ACT) remains a significant concern for most clinicians. Recently, genetic approach has been used to identify patients at increased risk of ACT. This systematic review assessed the association between genomic markers and ACT. A systematic literature search was performed in Medline, PubMed, Cochrane Central Register of Controlled Studies, CINAHL Plus, AMED, E ...[more]

PMID: 28232737

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Project description:Background Physical exercise is an intervention that might protect against doxorubicin-induced cardiotoxicity. In this meta-analysis and systematic review, we aimed to estimate the effect of exercise on doxorubicin-induced cardiotoxicity and to evaluate mechanisms underlying exercise-mediated cardioprotection using (pre)clinical evidence. Methods and Results We conducted a systematic search in PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases. Cochrane's and Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) risk-of-bias tools were used to assess the validity of human and animal studies, respectively. Cardiotoxicity outcomes reported by ≥3 studies were pooled and structured around the type of exercise intervention. Forty articles were included, of which 3 were clinical studies. Overall, in humans (sample sizes ranging from 24 to 61), results were indicative of exercise-mediated cardioprotection, yet they were not sufficient to establish whether physical exercise protects against doxorubicin-induced cardiotoxicity. In animal studies (n=37), a pooled analysis demonstrated that forced exercise interventions significantly mitigated in vivo and ex vivo doxorubicin-induced cardiotoxicity compared with nonexercised controls. Similar yet slightly smaller effects were found for voluntary exercise interventions. We identified oxidative stress and related pathways, and less doxorubicin accumulation as mechanisms underlying exercise-induced cardioprotection, of which the latter could act as an overarching mechanism. Conclusions Animal studies indicate that various exercise interventions can protect against doxorubicin-induced cardiotoxicity in rodents. Less doxorubicin accumulation in cardiac tissue could be a key underlying mechanism. Given the preclinical evidence and limited availability of clinical data, larger and methodologically rigorous clinical studies are needed to clarify the role of physical exercise in preventing cardiotoxicity in patients with cancer. Registration URL: https://www.crd.york.ac.uk/prospero; Unique identifier: CRD42019118218.

Project description:BackgroundDoxorubicin and other anthracycline derivatives inhibit topoisomerase II and is an important class of cytotoxic chemotherapy in cancer treatment. The use of anthracycline is limited by dose-dependent cardiotoxicity, which may manifest initially as asymptomatic cardiac dysfunction with subsequent progression to congestive heart failure. Despite baseline assessment and periodic monitoring of cardiac function for patients receiving anthracycline agents, there are unmet needs in prediction and prevention of anthracycline-induced cardiotoxicity (AIC).Case summaryA 35-year-old African American female was found to have a 9-cm high-grade osteosarcoma of right femur and normal baseline cardiac function with left ventricular ejection fraction of approximately 60%-70% determined by transthoracic and dobutamine stress echocardiogram. She underwent perioperative doxorubicin and cisplatin chemotherapy with 3 cycles before surgery and 3 cycles after surgery, and received a total of 450 mg/m2 doxorubicin at the end of her treatment course. She was evaluated regularly during chemotherapy without any cardiac or respiratory symptoms. Approximately two months after her last chemotherapy, the patient presented to the emergency department with dyspnea for one week and was intubated for acute hypoxic respiratory failure. Echocardiogram showed an ejection fraction of 5%-10% with severe biventricular failure. Despite attempts to optimize cardiac function, the patient's hemodynamic status continued to decline, and resuscitation was not successful on the seventh day of hospitalization. The autopsy showed no evidence of osteosarcoma, and the likely cause of death was cardiac failure with the evidence of pulmonary congestion, liver congestion, and multiple body cavity effusions.ConclusionWe present a case of 35-year-old African American female developing cardiogenic shock shortly after receiving a cumulative dose of 450 mg/m2 doxorubicin over 9 mo. Cardiac monitoring and management of patients receiving anthracycline chemotherapy have been an area of intense research since introduction of these agents in clinical practice. We have reviewed literature and recent advances in the prediction and prevention of AIC. Although risk factors currently identified can help stratify patients who need closer monitoring, there are limitations to our current understanding and further research is needed in this field.

Project description:ContextAlthough family studies have shown that male lower urinary tract symptoms (LUTS) are highly heritable, no systematic review exists of genetic polymorphisms tested for association with LUTS.ObjectiveTo systematically review and meta-analyze studies assessing candidate polymorphisms/genes tested for an association with LUTS, and to assess the strength, consistency, and potential for bias among pooled associations.Evidence acquisitionA systematic search of the PubMed and HuGE databases as well as abstracts of major urologic meetings was performed through to January 2013. Case-control studies reporting genetic associations in men with LUTS were included. Reviewers independently and in duplicate screened titles, abstracts, and full texts to determine eligibility, abstracted data, and assessed the credibility of pooled associations according to the interim Venice criteria. Authors were contacted for clarifications if needed. Meta-analyses were performed for variants assessed in more than two studies.Evidence synthesisWe identified 74 eligible studies containing data on 70 different genes. A total of 35 meta-analyses were performed with statistical significance in five (ACE, ELAC2, GSTM1, TERT, and VDR). The heterogeneity was high in three of these meta-analyses. The rs731236 variant of the vitamin D receptor had a protective effect for LUTS (odds ratio: 0.64; 95% confidence interval, 0.49-0.83) with moderate heterogeneity (I(2)=27.2%). No evidence for publication bias was identified. Limitations include wide-ranging phenotype definitions for LUTS and limited power in most meta-analyses to detect smaller effect sizes.ConclusionsFew putative genetic risk variants have been reliably replicated across populations. We found consistent evidence of a reduced risk of LUTS associated with the common rs731236 variant of the vitamin D receptor gene in our meta-analyses.Patient summaryCombining the results from all previous studies of genetic variants that may cause urinary symptoms in men, we found significant variants in five genes. Only one, a variant of the vitamin D receptor, was consistently protective across different populations.

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Candidate Gene Association Studies of Anthracycline-induced Cardiotoxicity: A Systematic Review and Meta-analysis.

Publications

Candidate Gene Association Studies of Anthracycline-induced Cardiotoxicity: A Systematic Review and Meta-analysis.

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