Abstract 685P
Background
Sunitinib is successfully used in the treatment of metastatic renal cell carcinoma (mRCC), although the individual response is highly variable. In candidate gene studies, sunitinib efficacy or toxicity was related to germline single nucleotide polymorphisms (SNPs) in CYP3A5 and ABCB1. The aim of this meta-analysis of genome-wide association studies (meta-GWAS) is to provide novel leads into biological mechanisms underlying sunitinib mechanism of action.
Methods
We included 550 mRCC patients that participated in the European EuroTARGET consortium and 219 mRCC patients from the RIKEN cohort in Japan. After SNP imputation using the 1000Genomes reference panel, SNPs were tested for association with progression-free survival (PFS) and overall survival (OS) using Cox regression. Summary statistics of both cohorts were combined using a fixed effect meta-analysis.
Results
In the EuroTARGET cohort, we identified novel genetic variants in PDLIM3 and DSCAM with genome wide significance (p<5x10-8) for association with PFS and OS. SNPs rs28520013 (PDLIM3) and the highly correlated variants rs2205096 and rs111356738 (DSCAM) remained significant (p<4.8×10-8) in the meta-analysis that includes the RIKEN cohort. The variant T-allele of rs28520013 associated with an inferior PFS of 5.1 months (CI95%: 1.5-6.2) compared with 12.5 months (95%CI: 10.9-14.9) in non-carriers (p=4.02×10-10, HR=7.26). T-allele carriers also showed an inferior OS of 6.9 months (95%CI: 5.5-27.6) compared with 30.2 months (95%CI: 27.4-33.4) for non-variant carriers (p=1.62×10-8, HR=5.96).
Conclusions
This meta-GWAS demonstrates that SNPs in PDLIM3 and DSCAM have a negative impact on PFS and OS in sunitinib-treated mRCC patients. The SNP rs28520013 is hypothesized to change PDLIM3 protein activity that regulates the NF-κB p65 subunit and thereby cytokine production. The DSCAM protein influences the function of p21-associated kinase (PAK) that also effects NF-κB. Genetic polymorphisms in genes encoding PDLIM3 and DSCAM may be involved in the PI3K/AKT signalling pathway by intervention with PAK or NF-κB, and possibly influence sunitinib efficacy.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
EuroTARGET consortium: A European collaborative project on TArgeted therapy in renal cell cancer-GEnetic- and tumor-related biomarkers for response and toxicity (EuroTARGET).
Funding
The research leading to these results has received funding from the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no 259939.
Disclosure
R.H. Mathijssen: Financial Interests, Personal and Institutional, Principal Investigator: Astellas; Financial Interests, Personal and Institutional, Principal Investigator: Bayer; Financial Interests, Personal and Institutional, Principal Investigator: Boehringer-Ingelheim; Financial Interests, Personal and Institutional, Principal Investigator: Cristal Therapeutics; Financial Interests, Personal and Institutional, Principal Investigator: Novartis; Financial Interests, Personal and Institutional, Principal Investigator: Pamgene; Financial Interests, Personal and Institutional, Principal Investigator: Pfizer; Financial Interests, Personal and Institutional, Principal Investigator: Roche; Financial Interests, Personal and Institutional, Principal Investigator: Sanofi; Financial Interests, Personal and Institutional, Principal Investigator: Servier. D. Castellano: Financial Interests, Personal, Advisory Board: Astellas; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Personal, Advisory Board: IPSEN; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Roche; Non-Financial Interests, Institutional, Principal Investigator: Astellas; Non-Financial Interests, Institutional, Principal Investigator: AstraZeneca; Non-Financial Interests, Institutional, Principal Investigator: Bayer; Non-Financial Interests, Institutional, Principal Investigator: BMS; Non-Financial Interests, Institutional, Principal Investigator: Clovis; Non-Financial Interests, Institutional, Principal Investigator: Eisai; Non-Financial Interests, Institutional, Principal Investigator: Exelisis; Non-Financial Interests, Institutional, Principal Investigator: GSK; Non-Financial Interests, Institutional, Principal Investigator: Ipsen; Non-Financial Interests, Institutional, Principal Investigator: Janssen; Non-Financial Interests, Institutional, Principal Investigator: Lilly; Non-Financial Interests, Institutional, Principal Investigator: MSD; Non-Financial Interests, Institutional, Principal Investigator: Pfizer; Non-Financial Interests, Institutional, Principal Investigator: QED; Non-Financial Interests, Institutional, Principal Investigator: Roche; Other, Institutional, Member: SOGUG (Spanish Oncology Genito-Urinary Group). All other authors have declared no conflicts of interest.