Abstract 947P
Background
The association between genetic variants and cisplatin nephrotoxicity has been studied previously using candidate gene approach but consistent results are lacking. We aimed to improve our understanding of genetic risk factors for cisplatin nephrotoxicity by identifying previously unreported genetic associations.
Methods
We conducted a meta-analysis of three genome-wide association studies of high-dose cisplatin-treated adults. Patients were diagnosed with head and neck cancer and esophageal cancer and recruited in Toronto, Canada. Nephrotoxicity was assessed between start of treatment and 90 days after cisplatin treatment had completed. Nephrotoxicity was based on following criteria: (i) increased serum creatinine according to Common Terminology Criteria for Adverse Events (CTCAE) v4.03 for acute kidney injury (AKI-CTCAE) and (ii) decreased estimated glomerular filtration rate (eGFR). Three different Illumina arrays were used for genotyping and standard quality control pre- and post-genotype imputation was applied.
Results
More than 6 million single nucleotide polymorphisms (SNPs) from 608 patients of European ancestry were evaluated. Five SNPs reached genome-wide significance. Rs4388268 (minor allele frequency=0.229), an intron variant SNP in the BACH2 gene was the most consistent single nucleotide polymorphism associated with increased risk of cisplatin nephrotoxicity in both outcomes and across the genotyping platforms: meeting genome-wide significance (β=-8.37, 95%CI -5.38 - -11.36, p=3.85x10-8) for decreased eGFR outcome and reaching near-significance level (OR=3.92, 95%CI 2.28-6.74, p=7.36x10-7) for AKI-CTCAE outcome. However, we couldn’t replicate the findings of our previously published candidate gene study although the association went to the same direction.
Conclusions
We found that rs4388268 in BACH2 increases the risk of nephrotoxicity nearly 4-folded in patients treated with cisplatin. So far, polymorphisms in BACH2 gene are known to be associated with several autoimmune diseases. Replication in an independent cohort and functional or pharmacokinetic validation are now needed before these findings can be utilized to personalize cisplatin therapy.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Geoffrey Liu.
Funding
Indonesia Endowment Fund for Education.
Disclosure
All authors have declared no conflicts of interest.