Changes in methylation associated with development of metabolic syndrome in testicular cancer patients treated with cisplatin chemotherapy.

Patients with metastatic testicular cancer (TC) treated with cisplatin-based chemotherapy (CBCT) are prone to develop metabolic syndrome (MetS). In an epigenome wide association study in patients with TC we have shown that DNA methylation was associated to CBCT. The aim of the study was to investigate whether there was a change in DNA methylation after treatment with CBCT, and if methylation status is related to the presence or development of MetS. In a prospective cohort of 67 TC patients who received CBCT, we assessed whole blood global methylation long interspersed nuclear element-1 (LINE-1) and DNA methylation at selected cytosine-phosphate-guanine dinucleotide (CpG) sites associated with MetS using targeted sequencing. Measured samples were taken before, one month after, and one year after CBCT. Development of MetS was assessed before and up to five years after CBCT. Serum platinum levels were measured to assess platinum exposure (PtAUC) within the first year after the start of CBCT. Data were used for paired comparisons, comparisons between groups, statistical modeling to account for covariates, and machine learning approaches to predict occurrence of MetS five years after diagnosis. Global methylation did not change during the first year after the start of CBCT (median 73.7% (25th -75th percentile 72.0-75.2) vs. 73.9% (72.5-75.1)). Seven out of the 16 other selected CpGs decreased. Patients with MetS before start of CBCT (N = 18) showed a larger decrease than patients without MetS (N = 49) for AC090023 (-11.6% vs. -8.2%, p = 0.008), NCAM2 (-6.5% vs. -1.6%, p = 0.030), and TOM1L2 (-5.8% vs. -2.6%, p = 0.003). The 15 patients who did not have MetS prior to CBCT, but developed MetS within five years after treatment showed an increase in global methylation (1.5% vs. - 0.6%, p = 0.008) after one year, and a decrease in TOM1L2 methylation (-4.0% vs. -1.6%, p = 0.015) when compared to patients who did not have prior to CBCT nor developed MetS (N = 34). There was no difference in PtAUC during the first year after the start of CBCT between the latter groups (70.0 vs. 67.9 days*mg/L, p = 0.206). Changes in global DNA methylation and TOM1L2 one year after the start of CBCT are associated with a higher risk for newly developing MetS within five years. This may indicate potential for tailored advice, based on epigenetic status, to patients treated with chemotherapy for TC to prevent development of MetS.