Molecular subtyping of gastric cancer combining genetic and epigenetic anomalies provides distinct clinicopathological features and prognostic impacts

: Both genetic and epigenetic abnormalities play important roles in gastric cancer (GC) development. We investigated whether the molecular subtypes of gastric cancer by combining genetic and epigenetic anomalies define its clinicopathological features and prognosis. The CpG island methylator phenotype (CIMP), MLH1 methylation, TP53, and KRAS mutation statuses were characterized in 214 GCs in relation to their clinicopathological features and prognosis. The molecular subtypes based on CIMP and TP53 hot spot mutation status (R175, G245, R248, R273, and R282) best predicted prognosis of GC. These subtypes contained 120 CIMP-positive (CIMP+) TP53 hot spot mutation-negative (TP53 hot spot-) cases, 81 CIMP-negative (CIMP-) TP53 hot spot- cases, 8 CIMP+TP53 hot spot mutation-positive (TP53 hot spot+) cases, and 5 CIMP- TP53 hot spot+ cases. The CIMP-TP53 hot spot+ group presented the worst overall survival (OS) and progression-free survival (PFS), followed by the CIMP+TP53 hot spot+, CIMP-TP53 hot spot- and CIMP+TP53 hot spot- groups (both P < 0.0001). These subtypes also correlated well with several aggressive clinicopathological features in that order. The molecular subtypes were independent factors for predicting overall survival (hazard ratio = 1.66, 95% CI = 1.07-2.57, P = 0.006). The molecular subtypes combining the CIMP and TP53 hot spot mutation status provide distinct clinicopathological features and prognostic impacts in GC.