156 Chapter 6 patients and controls, methylation levels of smokers and non-smokers were compared within both groups. The methylation levels did not significantly differ between smokers and non-smokers diagnosed with NSCLC. Likewise, methylation levels of smoking controls were comparable to non-smoking controls (Supplementary Figure 1). Control (n=50) NSCLC (n=44) 0 1 2 3 ✱ 5 Control (n=50) NSCLC (n=44) ✱✱✱ Control (n=50) NSCLC (n=44) ns Methylation level (sqrt Ct ratio) CDO1 SOX17 TAC1 Figure 1: Methylation levels in the urine supernatant samples. Methylation levels of markers CDO1, SOX17, and TAC1 in the urine supernatant of surgical NSCLC patients and controls. Data is depicted as the median with an interquartile range of square root transformed Ct ratios. The green and red circles represent the DNA methylation levels of individual controls and cases, respectively. A P-value of .05 was considered statistically significant. * = P<.05, *** = P<.001, ns = not significant. NSCLC = nonsmall cell lung cancer. DNA methylation levels in relation to disease severity and histology The methylation levels of each marker were compared between the different cancer stages and histological subtypes of NSCLC (Supplementary Figure 2). Due to low patient numbers in the stage II group (n=4), only stage I (n=28) could be compared with stage III (n=12). While CDO1 and TAC1 showed no significant difference between these stages, a trend toward higher methylation levels in stage I cases was seen for SOX17. In line with these findings, SOX17 levels were also found to be lower in tumors with lymph node involvement, which are overrepresented in the stage III group (Supplementary Figure 3). None of the markers showed a significant difference between the histological subtypes lung adenocarcinoma (LUAC, n=27) and lung squamous cell carcinoma (LUSC, n=16). The histological subtype not otherwise specified (NOS) could not be taken along in this comparison, due to the low number of patients in this group (n=1). Diagnostic performance of DNA methylation analysis for pre-operative NSCLC detection Univariate logistic regression analysis was performed and individual AUCs were calculated for each marker (Figure 2A). The AUCs obtained for CDO1, SOX17, and TAC1 were 0.68 (95% CI: 0.54-0.76), 0.72 (95% CI: 0.61-0.83), and 0.58 (95% CI: 0.46-0.69), respectively.
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