Exploring the contribution of genetic variants to high sunitinib exposure in patients with cancer.

AIMS: Sunitinib exhibits considerable interindividual variability in exposure. While the target total plasma concentration of sunitinib and its active metabolite is 50-87.5 ng/mL for the intermittent dosing schedule, ~10-21% of patients experience higher exposures (>87.5 ng/mL), correlated with an increased risk for toxicity. Previous research identified single nucleotide variants (SNVs) in genes from the sunitinib pharmacokinetic pathway to be associated with efficacy and toxicity. However, significant interindividual variability in exposure remains unexplained. Our aim was to identify genetic variants associated with supratherapeutic exposure of sunitinib. METHODS: This was a genome-wide association study. Cases were identified during routine therapeutic drug monitoring and consisted of patients with dose-normalized sunitinib plasma concentrations >87.5 ng/mL (intermittent dosing) or >75 ng/mL (continuous dosing). Controls were sampled from the historical cohort EuroTARGET who tolerated the standard dose of 50 mg in an intermittent schedule. SNVs were tested for an association with sunitinib exposure. A P-value ≤5 × 10-8 was considered significant and a P-value between 5 × 10-8 and 5 × 10-6 was considered suggestive. RESULTS: Sixty-nine cases and 345 controls were included for association analysis. One SNV (rs6923761), located on the gene glucagon-like peptide 1 receptor, was significantly associated with increased sunitinib exposure (P = 7.86 × 10-19). Twelve SNVs were suggestive for an association with sunitinib exposure (P ≤ 5 × 10-6). CONCLUSIONS: While rs6923671 is associated with high sunitinib exposure, the underlying mechanism is not yet clarified and warrants further investigation. We could not confirm the earlier found associations between SNVs in candidate genes involved in the pharmacokinetic pathway of sunitinib and its efficacy and toxicity.

An Association Study of Germline Variants in Bladder Cancer-Related Genes with the Prognosis of Non-Muscle Invasive Bladder Cancer.

BACKGROUND: Various germline genetic variants are associated with the prognosis of non-muscle invasive bladder cancer (NMIBC). Germline variants in genes frequently somatically mutated in bladder cancer have not been studied thoroughly in relation to risk of recurrence or progression in NMIBC. OBJECTIVE: To identify germline DNA variants in bladder carcinogenesis-related genes associated with recurrence or progression in NMIBC. METHODS: We analysed associations between single-nucleotide polymorphisms (SNPs) and NMIBC recurrence and progression using data from the Nijmegen Bladder Cancer Study (NBCS, 1,443 patients). We included 5,053 SNPs within 46 genes known to have mutation, overexpression or amplification in bladder cancer. We included all recurrences in the statistical analysis and performed both single variant analysis and gene-based analysis. SNPs and genes that showed significant or suggestive association (false discovery rate P value < 20%) were followed-up in independent cohorts for replication analysis, through eQTL analysis and tests for association of tumour expression levels with NMIBC recurrence and progression. RESULTS: Single variant analysis showed no statistically significant associations with recurrence or progression. In gene-based analysis, the aggregate effect of the 25 SNPs in the Cyclin D1 gene (CCND1) was statistically significantly associated with NMIBC recurrence (Punadj = 0.001, PFDR = 0.046), but not with progression (Punadj = 0.17, PFDR = 0.54). Validation analysis in independent cohorts did not confirm the association of CCND1 with NMIBC recurrence. CONCLUSIONS: We could not identify reproducible associations between common germline variants in bladder carcinogenesis-related genes and NMIBC recurrence or progression.