Abstract 4335: High incidence of POLE and POLD1 mutations in Chinese colorectal cancer patients identified by comprehensive genomic profiling
Authors: Chen Yinbo , Zhang Sen , Huang Wei , Guo Jun , Guo Weidong , Qiu Fabo , Deng Meihai , Cao Jingyu , Klempner Samuel J. , Yao Shun , Yao Jicheng , Mu Shou , Yao Ming , Wang Kai , Wang Weifeng 
Published: August 2018

Abstract
Introduction: The proofreading 3'-5' exonuclease activities of DNA polymerase-ϵ (POLE) and δ (POLD1) are critical for preventing mutations. POLE and POLD1 mutations can lead to high tumor mutational burdens (TMB), and predict responsiveness to immune checkpoint inhibitors (ICPI) in the absence of microsatellite instability (MSI). We therefore analyzed the genomic alterations of POLE and POLD1 in Chinese colorectal cancer (CRC) patients by comprehensive genome profiling (CGP).
Method: A cohort of 123 Chinese CRC patients (pts) comprising 76 males and 47 females (median age of 60) with both FFPE tumor samples and matched peripheral blood normal control were analyzed. The majority (40%) of the patients were stage IV, 26% were stage III, 18% were stage I/II and the rest were unknown. CGP was performed with a 450-gene panel. In addition to the genomic alterations, TMB and MSI were calculated by next-generation sequencing-based algorithms.
Result: CGP revealed a typical CRC mutation landscape with TP53 in 71%, APC in 70% and KRAS in 50% of the 123 Chinese pts. Fifteen percent of the pts (19/123) were MSI-H. Median TMB of all CRC pts was 11 muts/Mb, and the MSI-H subgroup had significantly higher TMB value compared to MSS subgroup (119 vs 10 muts/Mb, p-value is 1.5E-08). In total, 10% of the pts (12/123) harbored POLE and/or POLD1 known somatic mutations in the COSMIC database, including 10 POLE mutations in 8 pts and 7 POLD1 mutations in 7 pts. The 12 pts had a median age of 60 yrs (range 32-81), and 5/12 were females. Eight out of the 12 pts were associated with MSI-H. Additionally, 21 novel somatic short variants of uncertain significance (VUS) in 8 pts were detected (8/123=6.5%), and 5 pts were associated with MSI-H. Eight out of 123 Chinese CRC pts (6.5%) had POLE known mutations, which is significantly higher than 0.7% in Western population (p=9e-9). Four pts had loss-of-function (LOF) mutations. Two cases were POLE V411L associated with younger ages and the other two were truncations. All four CRC patients possess very high TMB compared to the whole cohort (305 vs 11 muts/Mb) while three of them are microsatellite stable (MSS) at stage III and IV.
Conclusion: Our small cohort suggests a higher incidence of known POLE and POLD1 mutations in Chinese CRC patients and warrants further study. Our results highlight the clinical utility of comprehensive genome profiling in identifying likely responders to immune checkpoint inhibitors.
Citation Format: Yinbo Chen, Sen Zhang, Wei Huang, Jun Guo, Weidong Guo, Fabo Qiu, Meihai Deng, Jingyu Cao, Samuel J. Klempner, Shun Yao, Jicheng Yao, Shou Mu, Ming Yao, Kai Wang, Weifeng Wang. High incidence of POLE and POLD1 mutations in Chinese colorectal cancer patients identified by comprehensive genomic profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4335.