Clinical Outcomes of Patients with Microsatellite-Unstable Colorectal Carcinomas Depend on L1 Methylation Level

The prognostic significance of microsatellite instability (MSI) in colorectal cancers (CRCs) has been addressed in many studies since the initial description of better survival rates in MSI-positive (MSI+) tumors than in MSI-negative (MSI-) tumors. Recent studies have demonstrated that a higher degree of hypomethylation of long interspersed nuclear element-1 (L1) is related to poor prognosis of CRCs and that a wide variation of L1 methylation levels exist within MSI+ CRCs. Our aim was to identify whether L1 and Alu methylation status could predict clinical outcomes within MSI+ CRCs. We analyzed 207 MSI+ CRCs for their methylation levels in L1 and Alu repetitive DNA elements using pyrosequencing and correlated them with clinicopathological information including survival data. Univariate survival analysis showed that low Alu methylation status (< 18.60 %) and low L1 methylation status (< 53.00 %) were significantly associated with shorter overall survival time (log-rank test, P = 0.009 and P < 0.001, respectively). Multivariate analysis using nine parameters (Alu methylation status, L1 methylation status, patient's age, disease stage [tumor, node, metastasis staging system], differentiation, Crohn-like lymphoid reaction, KRAS/BRAF mutation status, CpG island methylator phenotype [CIMP] status, and peritumoral lymphocytic infiltration), which were significantly prognostic in MSI+ CRCs, revealed that low L1 methylation status was an independent prognostic factor of MSI+ CRCs (P = 0.009), whereas low Alu methylation status was not. Clinical outcomes of MSI+ CRCs depend on L1 methylation status, suggesting that lower L1 methylation status serves as a significant prognostic parameter of adverse prognosis in MSI+ CRCs.