162 Chapter 6 patients in which the primary tumor was still present (33). In line with recent literature showing that CDO1, SOX17, and TAC1 are highly methylated in both LUAD and LUSC (17), similar methylation levels were found in both histological subtypes of NSCLC. Other studies investigating the use of urine for NSCLC detection focused mainly on oncogenic driver mutations or mutations that develop resistance to targeted therapies. Several studies have described the detection of clinically actionable mutations in urine, including EGFR (19, 24, 34-36) and KRAS (19), indicating the presence of NSCLCderived DNA in this body fluid. Interestingly, Yu et al. (36) found that the detection of EGFR mutations in urine was more accurate in predicting the outcome of NSCLC patients as compared to plasma. Furthermore, it has been demonstrated that urine allows detecting mutations that were sometimes not found in concordant tissue or plasma (37-39). Monitoring response to systemic therapy using urine ctDNA has also been examined for NSCLC (35, 40, 41). Hu et al. (35) examined the use of urine for the detection of early NSCLC relapses in EGFR-positive patients and found that elevated urine DNA concentrations after first-line therapy may already indicate the presence of minimal residual disease. These data underline the potential value of urine as a liquid biopsy for tumor response monitoring and the clinical management of NSCLC. To our knowledge, there is no data available about perioperative dynamics of methylated DNA in urine for lung cancer patients. In a small pilot of 14 patients, we investigated whether methylation levels alter after surgery with curative intent. Although we found a reduction in methylation levels of some markers post-operatively and in patients without recurrence, no conclusive results were obtained. Whether methylation analysis could be useful for therapy monitoring and the detection of disease recurrence warrants further investigation in larger cohorts using a broader panel of methylation markers. Currently, the MEDAL trial is ongoing, which is a prospective observational trial in which both plasma ctDNA mutations and methylation are utilized as prognostic biomarkers for surgical NSCLC patients (42). The current feasibility study has several limitations. Our control group consisted of healthy volunteers. Since age and sex could influence background methylation levels (43), the selection of controls was based on these characteristics. However, while almost all NSCLC patients had a smoking history (91%), only less than half of the control group reported a smoking history (40%). It is therefore possible that the methylation results obtained in the NSCLC group can at least partially be attributed to the general changes in DNA methylation patterns associated with tobacco use (44). Yet, in line with our findings, for methylation levels of CDO1, SOX17, and TAC1 in particular, independent studies have reported that methylation of these genes allow the prediction of NSCLC
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