PO-360 Epigenetic changes in testicular cancer survivors treated with cisplatin

Abstract

IntroductionTesticular germ cell cancer, hereafter called testicular cancer (TC), is the most common malignancy in young men in lagre parts of the world. Cisplatin-based chemotherapy (CBCT) has contributed to an increase in TC survival rates over the last decades. However, cisplatin exposure has been shown to result in drug-induced DNA hypermethylation. The aim of the present study is to study the effects of CBCT on DNA methylation in cisplatin-treated vs untreated TC survivors.Material and methodsWe included 279 Norwegian TC survivors, where 103 underwent orchiectomy, and 176 orchiectomy and additional CBCT. The two groups were matched on age at blood sampling. The TC survivors were re-examined on average 16 years after the orchiectomy. Whole genome DNA methylation profiles were measured with Illumina`s MethylationEPIC BeadChip and analysed with the R package minfi. We used a linear regression model adjusting for smoking, age and cell type composition to identify CBCT differentially methylated CpG sites. Additionally, genes with p-value<0.1, were used for gene enrichment analyses (GSEA) based on Fisher’s exact test using KEGG and Reactome pathways.Results and discussionsOut of the initial 866,836 CpG sites, 8 62 400 were included in our analysis. Thirty-three and 14 differentially methylated CpG sites were associated with CBCT after adjusting for multiple testing with False Discovery Rate (FDR) and Bonferroni correction, respectively. Eighty-five genes had a FDR adjusted p-value<0.1 and were used for GSEA. The ‘PTK6 regulates RHO GTPases, RAS GTPase and MAP kinases’ pathway was significantly (adjusted p-value<0.05) enriched with differential DNA methylated sites in three out of 26 genes. This pathway is part of signalling transduction related to several cell functions including growth, differentiation, division, survival and apoptosis. This is in concordance with the cytotoxicity of CBCT, and with the observation that it can be measured in serum many years after application in CBCT-treated patients.ConclusionOur results suggest that CBCT has long-term effects on the epigenome. Overall these results can contribute to elucidate what cellular mechanism are behind later consequences for TC survivors, like organotoxicity and metabolic syndrome. Our results should be further explored in a larger study of TC survivors treated with CBCT.