Abstract 5751: Comprehensive analysis of POLE/POLD1 variants, MMR deficient/MSI, and tumor mutational burden in Chinese population
Authors: Jia Yongning , Xin Yaqun , Yuan Hongling , Pang Fei , Shan Fei , Li Shuangxi , Zhu Honglin , Li Ziyu 
Published: June 2022

Background: Mutations in genes encoding DNA polymerase epsilon (POLE) and delta 1 (POLD1) can lead to defects in the DNA replication, resulting in a hypermutated tumor phenotype, which might help identify potential responders to immunotherapy. This study aims to comprehensively investigate the different variants of POLE/POLD1 mutants and how it related to MSI/MMR status and TMB levels within a large Chinese population.

Methods:Among 15640 Chinese patients who underwent NGS testing, the prevalence of POLE/POLD1 mutants was analyzed and the high frequencies of POLE/POLD1 variants as well as their relations with MMR/MSI and TMB were explored.

Results: POLE and POLD1 mutations were highly distributed in endometrial cancer (11.1% and 9.3%), colorectal cancer (5.9% and 4.5%), and gastric cancer (4.6% and 3.3%). In our study, the mutation frequency of POLE was 3.4%, including p.Ala252Val (9.2%), p.Pro286Arg (2.7%), p.Val411Leu (1.3%), p.Asp601Glu (6.0%), p.Lys425Gln (2.9%) and p.Phe1849Val (1.8%). Variants of p.Ala252Val, p.Pro286Arg and p.Val411Leu displayed high TMB levels (median 71.4 muts/Mb, 236.7 muts/Mb and 220 muts/Mb, respectively) while variants of p.Asp601Glu, p.Lys425Gln, p.Phe1849Val and p.Asn2098His had a rather low TMB, ranging from 5.2-8.1 muts/Mb. It is worth mentioning that 37.5% of p. Pro286Arg and 87.5% of Val411Leu variants had concurrent loss-of-function mutations of MMR (MMRLOF), while MMRLOF rarely occurred in the other variants.For POLD1, the mutation frequency in Chinese patients was 2.8%, including p.Arg119His (18.8%), p.Glu57del (16.5%) and p.Asp987Thrfs (3.3%). p.Arg119His variants showed a high TMB level of 65.6 muts/Mb and most occurred in lung cancer. Variants of p.Asp987Thrfs, p.Pro116Hisfs and p.Arg19His had similar TMB levels (p&gt;0.05), while much lower TMB levels was found in p.Glu57del (3.3 muts/Mb, p&lt;0.001) compared to p.Arg119His.Compared with POLE/POLD1 wild-type (POLDE/POLD1-WT), the percentage of MSI-H samples in POLE/POLD1 mutants was much higher (14% vs 0.7, p&lt;0.001). About 10% of POLE/POLD1 mutations carried MMRLOF mutations while it was barely observed in POLE/POLD1-WT (0.5%). The TMB levels of POLE/POLD1 mutations were significantly higher than that of the POLE/POLD1-WT (17.7 vs 2.9 muts/Mb, p&lt;0.001). Furthermore, POLE/POLD1 mutations was found to be a main cause leading to high levels of TMB. Among samples with TMB &gt;10 muts/Mb, 22.6% of them were POLE/POLD1 mutations. And in samples with TMB &gt;100 muts/Mb, as high as 82% of samples were found carrying POLE/POLD1 mutations.

Conclusion: POLE/POLD1 mutations were found in Chinese patients in multiple tumors. Different POLE/POLD1 variants were associated with different MMR status and TMB levels. In addition to MMR, POLE/POLD1 mutations might be another distinct means of inducing high TMB.

Citation Format: Yongning Jia, Yaqun Xin, Hongling Yuan, Fei Pang, Fei Shan, Shuangxi Li, Honglin Zhu, Ziyu Li. Comprehensive analysis of POLE/POLD1 variants, MMR deficient/MSI, and tumor mutational burden in Chinese population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5751.