Genetic variants in SLC22A17 and SLC22A7 are associated with anthracycline-induced cardiotoxicity in children

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From: Pharmacogenomics(Vol. 16, Issue 10)
Publisher: Future Medicine Ltd.
Document Type: Article
Length: 8,675 words
Lexile Measure: 1770L

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Author(s): Henk Visscher aff1 , S Rod Rassekh aff2 , George S Sandor aff3 , Huib N Caron aff4 , Elvira C van Dalen aff4 , Leontien C Kremer aff4 , Helena J van der Pal aff4 aff5 , Paul C Rogers aff2 , Michael J Rieder aff6 , Bruce C Carleton aff7 , Michael R Hayden aff1 , Colin J Ross [*] aff1 aff7

Keywords:

anthracyclines; association study; cardiotoxicity; childhood cancer; pharmacogenomics

Background

Anthracycline-induced cardiotoxicity (ACT) is one of the most serious adverse drug reactions in childhood cancer therapy with potential life-long consequences causing substantial morbidity and mortality, as well as limiting anthracycline use [1-3 ]. Nevertheless, anthracyclines are widely used - nearly 60% of childhood cancer patients receive anthracyclines - and anthracyclines have been key in improving cancer survival rates [2 ].

Anthracycline cardiotoxicity can occur early - during or within 1 year after therapy - or late, occurring one or many years after treatment [3 ]. ACT manifests as asymptomatic subclinical left ventricular dysfunction that is usually diagnosed using echocardiography in up to 57% of patients. ACT can be progressive [4-6 ] leading to severe clinical heart failure requiring treatment in up to 16% of patients [2,7-9 ].

Identification of patients at higher risk for ACT is important to allow for risk stratification that can inform treatment and monitoring options. Multiple clinical risk factors for ACT have been identified, most importantly higher cumulative anthracycline doses and concomitant cardiac irradiation, with some of these known for decades [2-10 ]. More recently, several studies have started to unravel the genetic susceptibility to ACT - including in children - though only few variants have been replicated in independent cohorts [11-17 ]. We recently identified and replicated genetic variants that are predictive of ACT in SLC28A3 and UGT1A6 and found evidence for association of variants in SULT2B1, SLC28A1 and ABCB4 [16,17 ]. Combining these variants with clinical risk factors into a risk prediction model allowed for significantly better discrimination between cases and controls than clinical factors alone [16,17 ].

Nevertheless, additional genetic susceptibility variants might exist that could further improve the prediction of ACT. To identify and replicate additional variants predictive of ACT, we conducted a study using an extended genotyping panel including over 4500 SNPs in more than 300 genes preselected for relevance in pharmacokinetics and dynamics, including genes relevant for anthracycline transport, metabolism and toxicity. We enrolled a large cohort of children treated with anthracyclines with further replication in an independent cohort of pediatric cancer patients, and assessed whether the addition of newly identified variants would improve the risk prediction model.

Patients & methods

Samples

Study participants were recruited through the Canadian Pharmacogenomics Network for Drug Safety (CPNDS), a multicenter active surveillance and pharmacogenomics research consortium studying adverse drug reactions in children [18 ]. The discovery cohort (n = 344) comprised patients recruited from pediatric oncology units and long-term follow-up clinics across Canada between February 2005 and January 2010 and comprised the two Canadian cohorts combined that were used previously to identify variants associated with ACT [16 ]. The replication cohort (n...

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Gale Document Number: GALE|A428534840