Abstract
Werner syndrome gene (WRN) contributes to DNA repair. In cancer, WRN mutations (WRN-mut) lead to genomic instability. Thus, WRN is a promising target in cancers with microsatellite instability (MSI). We assessed this study to investigate the molecular profile of WRN-mut in colorectal cancer (CRC). Tumor samples were analyzed using next-generation sequencing (NGS) in-situ hybridization and immunohistochemistry. Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations. Determination of tumor mismatch repair (MMR) or microsatellite instability (MSI) status was conducted by fragment analysis. WRN-mut were detected in 80 of 6854 samples (1.2%). WRN-mut were more prevalent in right-sided compared to left-sided CRC (2.5% vs. 0.7%, p < 0.0001). TMB, PD-L1 and MSI-H/dMMR were significantly higher in WRN-mut than in WRN wild-type (WRN-wt). WRN-mut were associated with a higher TMB in the MSI-H/dMMR and in the MSS (microsatellite stable) subgroups. Several genetic differences between WRN-mut and WRN-wt CRC were observed, i.e., TP53 (47% vs. 71%), KRAS (34% vs. 49%) and APC (56% vs. 73%). This is the largest molecular profiling study investigating the genetic landscape of WRN-mut CRCs so far. A high prevalence of MSI-H/dMMR, higher TMB and PD-L1 in WRN-mut tumors were observed. Our data might serve as an additional selection tool for trials testing immune checkpoint antibodies in WRN-mut CRC.
Highlights
Colorectal cancer (CRC) is the second most diagnosed cancer in women and the third in men
All tests were two-sided at a significance level of 0.05. As this is an exploratory study, no correction for multiple comparison was performed. This is the largest profiling study investigating the molecular landscape of Werner syndrome gene (WRN)-mut colorectal cancer (CRC)
We show an association between microsatellite instability (MSI)-H/dMMR status and WRN-mutation as well as a link to higher Tumor mutational burden (TMB) and Programmed Death-ligand 1 (PD-L1) expression
Summary
Colorectal cancer (CRC) is the second most diagnosed cancer in women and the third in men. There is an unmet clinical need for improvement of therapy. Transcriptomics and proteomics, the translation of these findings into clinical routine treatment regimens in CRC has been rarely successful. Treatment with inhibitors of the immune checkpoint Programmed Death-1 (PD-1)/Programmed Death-Ligand. 1 (PD-L1) led to substantial improvements in the prognosis of metastatic melanoma [2] and lung cancer patients [3]. In CRC, only a subset of patients, namely those with a damaged DNA mismatch repair gene and/or a microsatellite instability (MSI-H/dMMR), seem to benefit from a treatment with checkpoint inhibitors [4,5]. An MSI-H/dMMR state is observed in approximately 5–15% of all sporadic
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