Abstract 359P
Background
POLE (DNA Polymerase Epsilon, Catalytic Subunit) is a protein coding gene. This gene encodes the catalytic subunit of DNA polymerase epsilon, involved in DNA repair and chromosomal DNA replication. Mutations in this gene, especially related to proofreading defects in the POLE polymerase (POLE pd), have been associated with hypermutated genomes and sensitive response by checkpoint blocking immunotherapies for colorectal cancer (CRC). The profile of Tumor mutation burden (TMB) and tumor microenvironment between POLE mutation(POLEmut) and POLE wildtype(POLEwt) CRC is not clearly elaborated.
Methods
Mutation,TMB and MSI data of 6489 FFPE tumor samples from Chinese CRC patients were sequenced by targeted next-generation sequencing (NGS, 3DMed panel). Pathogenic variants, very like pathogenic mutations and variants of unknown significance of POLE were classified as POLEmut. Tumor microenvironment (TME) data of 162 CRC patients was conducted by multiplex immunofluorescence (mIF). The association between POLE mutation and TMB/TME in CRC were explored.
Results
In total, 6.3%(411/6489) of CRC patients were identified as POLEmut. TMB of POLEmut was significantly higher than POLEwt CRC either include MSI-H (154.70/MB vs 9.86/MB, p=5.25×10-63) or exclude MSI-H (179.11/MB vs 6.88/MB, p=1.78×10-38). Especially, TMB of POLEpd (94/411) was significantly higher than non-POLEpd (319/411) among POLEmut CRC either include MSI-H(269.88/MB vs 121.01/MB, p=7.82×10-18) or exclude MSI-H (270.15/MB vs 123.53/MB, p=2.57×10-6). Worth mentioned, 64 hotspots in non-POLEpd/MSS CRC were identified to be related to high TMB(>100/MB). Analysis of TME found that CD56 bright (immaturated NK) cells were significantly higher in POLEwt CRC both in tumoral and stromal region (p=0.025 and p=0.012).
Conclusions
POLE gene mutation was associated with higher TMB level in CRC and had different TME. POLE is a potential biomarker for immunotherapy of CRC , and efficacy of different hotspots warren further study.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.