Genome-Wide Meta-Analysis Identifies Variants in DSCAM and PDLIM3 That Correlate with Efficacy Outcomes in Metastatic Renal Cell Carcinoma Patients Treated with Sunitinib

Meta H.M. Diekstra*, Jesse J. Swen, Loes F.M. van der Zanden, Sita H. Vermeulen, Epie Boven, Ron H.J. Mathijssen, Koya Fukunaga, Taisei Mushiroda, Fumiya Hongo, Egbert Oosterwijk, Anne Cambon-Thomsen, Daniel Castellano, Achim Fritsch, Jesus Garcia Donas, Cristina Rodriguez-Antona, Rob Ruijtenbeek, Marius T. Radu, Tim Eisen, Kerstin Junker, Max RoesslerUlrich Jaehde, Tsuneharu Miki, Stefan Böhringer, Michiaki Kubo, Lambertus A.L.M. Kiemeney, Henk Jan Guchelaar

*Corresponding author for this work

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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.

Original languageEnglish
Article number2838
JournalCancers
Volume14
Issue number12
DOIs
Publication statusPublished - 8 Jun 2022

Bibliographical note

Funding Information:
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.

Funding Information:
Conflicts of Interest: Ron HJ Mathijssen received unrestricted grants for investigator-initiated research from Astellas, Bayer, Boehringer-Ingelheim, Cristal Therapeutics, Novartis, Pamgene, Pfizer, Roche, Sanofi, and Servier. Daniel Castellano reported personal financial interests in Astellas, Astra Zeneca, BMS, GSK, Ipsen, Janssen, MSD, Novartis, Pfizer, and Roche. As a local PI Daniel Castellano reported to have no financial interest in Astellas, Astra Zeneca, Bayer, BMS, Clovis, EISAI, Exelisis, GSK, Ipsen, Janssen, Lilly, MSD, Pfizer, QED, and Roche. Further, he reported non-financial interests for SOGUG (the Spanish Oncology Genito-Urinary Group). Jesus Garcia Donas reported financial interests in research funding from Astra Zeneca, BMS, GSK, Ipsen, Janssen, MSD, Novartis, Pfizer, Roche, Bayer, and Clovis. The other authors have no conflicts of interest to declare. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Other authors declare no conflict of interest.

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

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