645PWRN mutated colorectal cancer (CRC) is characterized by a distinct molecular and immunological profile

Abstract Background Werner syndrome gene (WRN) encodes a DNA helicase with an exonuclease activity that contributes to DNA repair. In cancer, WRN mutations lead to genomic instability. It is known that WRN is necessary to sustain in-vivo growth of cancers cells with microsatellite instability (MSI), including CRC. WRN is a very promising new target especially in cancers with MSI. There is still a lack of knowledge about the frequency of WRN alterations and their association with immunological and molecular phenotypes. Methods Tumour samples from 6854 CRC patients were analyzed using NGS (NextSEQ on 592 genes), in-situ hybridization and immunohistochemistry (Caris Life Sciences, Phoenix, AZ, USA). Tumour mutational burden (TMB) was calculated based on somatic non-synonymous missense mutations, and MSI was evaluated by NGS of known MSI loci. Results WRN mutations (WRN-mut) were observed in 80 of 6854 samples (1.2%). A higher prevalence of WRN-mut was detected in right- compared to left-sided CRC (2.4% vs 0.7%, p Conclusions This is the largest profiling study to investigate the molecular and immunological landscape of WRN-mut CRCs. We show the high prevalence of MSI in WRN-mut tumours and their association with higher TMB and PD-L1 expression. Furthermore, it revealed that WRN-mut CRC is characterized by a distinct genetic profile. Our data might serve to tailor treatment in WRN-mut CRC. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.