LINE-1 hypo-methylation as a distinct phenotype in non-EBV/non-MSI-H esophagogastric junction adenocarcinoma.

Abstract

411 Background: Most esophagogastric junction (EGJ) adenocarcinoma exhibits chromosomal instability (CIN) type with wide range of CpG site methylation. However, it is still uncertain if epigenetic alteration is clinically useful. LINE-1 methylation level is representative of genome-wide methylation status. The aim of this is to examine clinicopathological and molecular characteristics of LINE-1 methylation, and its prognostic role, in non-EBV/non-MSI-H EGJ adenocarcinoma. Methods: After removing EBV-associated or MSI-H tumors, which are the distinct molecular subtype with hyper methylation, a total 335 case of chemo-naïve non-EBV/non-MSI-H EGJ adenocarcinoma from four academic institutions in Japan, were eligible. LINE-1 methylation was examined by Pyrosequencing. Results: LINE-1 methylation level was successfully sequenced in 319 cases (92.5%). LINE-1 methylation level was associate with tumor differentiation. Intestinal type was frequently observed in the lowest quartile Q1 cases (P = 0.0006). Of note, TP53 mutation rate was significantly frequent in Q1-2 cases (P < 0.0001). Ki-67 index was also higher in Q1-2 cases. Tumor PD-L1 expression, or CD8+ cell infiltration was not associated with LINE-1 methylation level. In survival analysis, the patients with the lowest LINE-1 methylation level (Q1), experienced the worst outcome in disease-specific survival, relapse-free survival, and overall survival rates. Conclusions: Tumor with LINE-1 hypomethylation harbors significantly higher TP53 mutation and higher Ki-67 index, resulting in worse outcome in EGJ adenocarcinoma patients.