Systematic review of pharmacogenomics and adverse drug reactions in paediatric oncology patients

Abstract

Many paediatric patients with cancer experience significant chemotherapy side effects. Predisposition to drug reactions is governed by single nucleotide polymorphisms (SNPs). We performed a systematic review of the literature from 2006 through 2016. Outcomes of interest included patient characteristics, cancer type drug of interest, genes investigated, toxicity identified and genetic polymorphisms implicated. The primary toxicities studied were neurotoxicity cardiotoxicity, osteonecrosis, and thromboembolism and hypersensitivity reactions. The retrieved studies were grouped according to toxicity reported and SNP associations. This review highlights the discoveries to date in pharmacogenomics and paediatric oncology along with highlighting some of the important limitations in the area.

Pharmacology and pharmacogenetics of prednisone and prednisolone in patients with nephrotic syndrome

“…The interpretation of the influence of the genetic polymorphisms on P-glycoprotein expression, however, is unresolved and may vary depending on tissue type, pathological status, and ethnicity [118]. A recent systematic review on pharmacogenetics and adverse drug reactions in pediatric oncology patients indicated protective effects from two genetic polymorphisms of the MDR1 gene in methotrexate-and vincristine-related neurotoxicity in pediatric ALL patients [119]. In nephrotic syndrome patients, however, no studies have been conducted to investigate the potential role of genetic polymorphisms in the MDR1 gene in steroid-related toxicities.…”

Pharmacogenomics as a Tool to Limit Acute and Long-Term Adverse Effects of Chemotherapeutics: An Update in Pediatric Oncology

“…Past studies showed a strong association between genetic variations SLC28A3 (rs7853758 and rs885004) and detoxifying uridine diphosphate glucuronosyl transferase (UGT) UGT1A6*4 (rs17863783) and anthracycline-induced cardiotoxicity (Visscher et al, 2013;Aminkeng et al, 2016). Also genetic variations in CBR3 (Blanco et al, 2012;Visscher et al, 2012), ABCC1 (rs3743527, rs246221) (Blanco et al, 2008), SLC28A3 (rs885004 and rs4877847), SLC22A17 (rs4982753, rs4149178) (Visscher et al, 2015), and sulfotransferase (SULT) SULT2B1 (rs12882406 and rs12896494) (Visscher et al, 2015) have been associated with cardiotoxicity during anthracycline treatment (Conyers et al, 2018). In recent years, three studies have focused on ABCB1, ABCC1, ABCC2, ABCC5, ABCG2, SLC28A3, and CYP3A5 (Krajinovic et al, 2016;Huang et al, 2017;Ruiz-Pinto et al, 2017).…”

“…Pharmacogenomics: Update in Pediatric Oncology et al, 2015; Aminkeng et al, 2016;Conyers et al, 2018). However, results in relation to these gene variants and anthracycline-induced cardiotoxicity remain inconsistent.…”

“…Three variant alleles TPMT*2 (G238C), TPMT*3A (G460A and A719G) and TPMT*3C (A719G), account for more than 95% of the inherited variability in TPMT enzyme activity (Conyers et al, 2018), although more TPMT deficient variants have recently been identified, with a less frequent occurrence (Koutsilieri et al, 2019).…”

“…Genetic variants involved in ROS prevention have received much attention in past studies ( Aminkeng et al., 2016 ; Bansal et al., 2017 ; Chang and Wang, 2018 ). These include genetic variations in NADPH oxidase, Ras-related C3 botulinum toxin substrate 2 ( RAC2) ( Aminkeng et al., 2015 ), neutrophil cytosolic factor 4 ( NCF4) ( Visscher et al., 2012 ), Cytochrome B-245 Alpha Chain ( CYBA) ( Visscher et al., 2012 ; Windsor et al., 2012 ; Armenian et al., 2013 ) and catalase (CAT) ( Rajić et al., 2009 ; Aminkeng et al., 2015 ; Aminkeng et al., 2016 ; Conyers et al., 2018 ). However, results in relation to these gene variants and anthracycline-induced cardiotoxicity remain inconsistent.…”