Abstract
This study aims to evaluate genetic risk factors for cisplatin-induced nephrotoxicity by investigating not previously studied genetic risk variants and further examining previously reported genetic associations. A genome-wide study (GWAS) was conducted in genetically estimated Europeans in a discovery cohort of cisplatin-treated adults from Toronto, Canada, followed by a candidate gene approach in a validation cohort from the Netherlands. In addition, previously reported genetic associations were further examined in both the discovery and validation cohorts. The outcome, nephrotoxicity, was assessed in two ways: (i) decreased estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) and (ii) increased serum creatinine according to the Common Terminology Criteria for Adverse Events v4.03 for acute kidney injury (AKI-CTCAE). Four different Illumina arrays were used for genotyping. Standard quality control was applied for pre- and post-genotype imputation data. In the discovery cohort (n = 608), five single-nucleotide polymorphisms (SNPs) reached genome-wide significance. The A allele in rs4388268 (minor allele frequency = 0.23), an intronic variant of the BACH2 gene, was consistently associated with increased risk of cisplatin-induced nephrotoxicity in both definitions, meeting genome-wide significance (β = −8.4, 95% CI −11.4–−5.4, p = 3.9 × 10−8) for decreased eGFR and reaching suggestive association (OR = 3.9, 95% CI 2.3–6.7, p = 7.4 × 10−7) by AKI-CTCAE. In the validation cohort of 149 patients, this variant was identified with the same direction of effect (eGFR: β = −1.5, 95% CI −5.3–2.4, AKI-CTCAE: OR = 1.7, 95% CI 0.8–3.5). Findings of our previously published candidate gene study could not be confirmed after correction for multiple testing. Genetic predisposition of BACH2 (rs4388268) might be important in the development of cisplatin-induced nephrotoxicity, indicating opportunities for mechanistic understanding, tailored therapy and preventive strategies.
Highlights
Since its approval by the FDA in 1978 [1], cisplatin has remained a backbone antineoplastic agent used to treat various cancers, such as head and neck, ovarian, testicular, cervical, bladder, gastroesophageal, breast and lung cancer [2,3]
This is the first GWAS with a validation study in an independent cohort exploring the association between genetic variants and cisplatin-induced nephrotoxicity in cancer patients. rs4388268, an intron variant single-nucleotide polymorphisms (SNPs) in the BACH2 gene, warrants further investigation due to its consistent association with increased risk of cisplatininduced nephrotoxicity in both AKI-CTCAE and estimated glomerular filtration rate (eGFR) outcomes and in both discovery and validation cohorts of European ancestry patients
From five SNPs identified from systematic review, only ERCC1 rs3212986 was associated with a higher risk of cisplatin-induced nephrotoxicity in the validation cohort of NSCLC patients
Summary
Since its approval by the FDA in 1978 [1], cisplatin has remained a backbone antineoplastic agent used to treat various cancers, such as head and neck, ovarian, testicular, cervical, bladder, gastroesophageal, breast and lung cancer [2,3]. Cisplatin causes endoplasmic reticulum and mitochondria dysfunction [4]. Its effectiveness coincides with numerous acute and long-term adverse effects [4,5] such as bone marrow suppression, nausea and vomiting, nephrotoxicity, ototoxicity, and neurotoxicity, which may hamper the antineoplastic potential for the individual patient [2,6]. Nephrotoxicity can lead to various renal manifestations such as acute kidney injury, hypomagnesemia, distal renal tubular acidosis, hypocalcemia, renal salt wasting, renal concentrating defect, hyperuricemia, transient proteinuria, erythropoietin
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