Somatic POLE proofreading domain mutations by next generation sequencing to predict outcomes in stage II colorectal cancer.
559 Background: Stage II colorectal cancers (CRC) exhibit unique molecular heterogeneity and patients with somatic POLE mutations are defined as a distinct tumor subgroup. The aim of this study was to clarify the characteristics and prognostic effect of somatic POLE proofreading domain mutations by Next Generation Sequencing in stage II CRC. Methods: Recurrent patients were 1:1 matched to patient with no recurrence for stage II CRC patients diagnosed between 2008 and 2013 in Fudan University Shanghai Cancer Center (FUSCC). All patients were pathologically confirmed and received radical resection. Microsatellite instability status and POLE mutation status were determined by NGS using ColonCore panel (Burning Rock, Guangzhou, China). Groups based on NGS-POLE mutation status were compared in terms of patient demographics and pathologic features using chi-squared tests. Survival curves were plotted using the Kaplan-Meier method. Results: In total, 245 stage II CRC patients were enrolled. POLE mutations were detected in 25 (10.2%) of 245 stage II CRC, while only 9 (3.7%) was located in proofreading domain (NGS-POLE EDM-mutations) and other 16 were found in non-proofreading domain (non-NGS-POLE mutations). Compared to cases with wild-type POLE, cases with NGS-POLE EDM-mutations were more prone to be microsatellite instability-high (MSI-H) (3 of 9 [33.3%] vs. 23 of 236 [9.7%], p = 0.024), younger at diagnosis (median 46 years vs. 62 years, p < 0.001), and more frequently with right-sided tumor location (6 of 9 [66.7%] vs. 54 of 236 [22.9%]; p = 0.003). All tumors with NGS-POLE EDM-mutations presented with a surprisingly high tumor mutation burden (TMB) (median 145.2 per Mb). Patients with NGS-POLE EDM-mutations have favorable 5-year disease-free survival (DFS) compared with those with non-NGS-POLE EDM-mutations and wild-type POLE (100% vs. 62.5% vs. 52.5%, p = 0.037). Though there is DFS difference between patients with non-NGS-POLE EDM-mutations and wild-type POLE, the difference was not statistically significant (p = 0.412). Conclusions: Stage II CRC patients with NGS-POLE EDM-mutation identify a special cancer subset with better immune environment predicting excellent outcomes.