Find in Library

Colorectal cancer (CRC) is one of the most common cancers and the second leading cause of cancer-related deaths. Discrepancies in clinical outcomes are observed even among patients with same-stage CRC due to molecular heterogeneity. Thus, biomarkers for predicting prognosis in CRC patients are urgently needed. We previously demonstrated that stage II CRC patients with <i>NKX6.1</i> methylation had poor 5-year overall survival. However, the methylation frequency of <i>NKX6.1</i> was only 23% in 151 pairs of CRC tissues. Thus, we aimed to develop a more robust prognostic panel for CRC using <i>NKX6.1</i> in combination with three genes: <i>LIM homeobox transcription factor 1α</i> (<i>LMX1A</i>), <i>sex-determining region Y-box 1</i> (<i>SOX1</i>), and <i>zinc finger protein 177</i> (<i>ZNF177</i>). Through quantitative methylation analysis, we found that <i>LMX1A</i>, <i>SOX1</i>, and <i>ZNF177</i> were hypermethylated in CRC tissues. <i>LMX1A</i> methylation was significantly associated with poor 5-year overall, and disease-free survivals in stage I and II CRC patients. Sensitivity and specificity analyses of the four-gene combination revealed the best sensitivity and optimal specificity. Moreover, patients with the four-gene methylation profile exhibited poorer disease-free survival than those without methylation. A significant effect of the four-gene methylation status on overall survival and disease-free survival was observed in early stage I and II CRC patients (<i>p</i> = 0.0016 and <i>p</i> = 0.0230, respectively). Taken together, these results demonstrate that the combination of the methylation statuses of <i>NKX6.1</i>, <i>LMX1A</i>, <i>SOX1</i>, and <i>ZNF177</i> creates a novel prognostic panel that could be considered a molecular marker for outcomes in CRC patients.