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Genome-Wide Meta-Analysis Identifies Variants in DSCAM and PDLIM3 That Correlate with Efficacy Outcomes in Metastatic
Meta H M Diekstra1,2, Jesse J Swen2, Loes F M van der Zanden3
1Department of Pharmacology, Princess Maxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands.
Abstract:
Individual response to sunitinib in metastatic renal cell carcinoma (mRCC) patients is highly variable. Earlier, sunitinib outcome was related to single nucleotide polymorphisms (SNPs) in CYP3A5 and ABCB1. Our aim is to provide novel insights into biological mechanisms underlying sunitinib action. We included mRCC patients from the European EuroTARGET consortium (n = 550) and the RIKEN cohort in Japan (n = 204) which were analysed separately and in a meta-analysis of genome-wide association studies (GWAS). SNPs were tested for association with progression-free survival (PFS) and overall survival (OS) using Cox regression. Summary statistics were combined using a fixed effect meta-analysis. SNP rs28520013 in PDLIM3 and the correlated SNPs rs2205096 and rs111356738 both in DSCAM, showed genome-wide significance (p < 5 × 10−8) with PFS and OS in the meta-analysis. The variant T-allele of rs28520013 associated with an inferior PFS of 5.1 months compared to 12.5 months in non-carriers (p = 4.02 × 10−10, HR = 7.26). T-allele carriers of rs28520013 showed an inferior OS of 6.9 months versus 30.2 months in non-carriers (p = 1.62 × 10−8, HR = 5.96). In this GWAS we identified novel genetic variants in PDLIM3 and DSCAM that impact PFS and OS in mRCC patients receiving sunitinib. The underlying link between the identified genes and the molecular mechanisms of sunitinib action needs to be elucidated.
Insights
New genetic markers in PDLIM3 and DSCAM influence sunitinib treatment outcomes for metastatic renal cell carcinoma (mRCC) patients. These findings offer insights into sunitinib
Area of Science:
- Genetics
- Oncology
- Pharmacogenomics
Background:
- Individual response to sunitinib in metastatic renal cell carcinoma (mRCC) is highly variable.
- Previous studies linked sunitinib outcomes to single nucleotide polymorphisms (SNPs) in CYP3A5 and ABCB1.
Purpose of the Study:
- To identify novel genetic variants impacting sunitinib efficacy in mRCC.
- To elucidate biological mechanisms underlying sunitinib action through genome-wide association studies (GWAS).
Main Methods:
- Meta-analysis of genome-wide association studies (GWAS) including European (n=550) and Japanese (n=204) mRCC cohorts.
- Cox regression analysis to assess the association of SNPs with progression-free survival (PFS) and overall survival (OS).
- Fixed effect meta-analysis to combine summary statistics.
Main Results:
- Genome-wide significant associations (p < 5 × 10−8) were found for SNP rs28520013 (PDLIM3) and correlated SNPs rs2205096/rs111356738 (DSCAM) with PFS and OS.
- The T-allele of rs28520013 was associated with significantly inferior PFS (5.1 vs. 12.5 months) and OS (6.9 vs. 30.2 months).
Conclusions:
- Novel genetic variants in PDLIM3 and DSCAM significantly impact PFS and OS in mRCC patients treated with sunitinib.
- Further research is needed to understand the molecular mechanisms linking these genes to sunitinib action.
