WRN -Mutated Colorectal Cancer Is Characterized by a Distinct Genetic Phenotype

• Published in: Cancers Vol. 12; no. 5; p. 1319
• Main Authors: Zimmer, Kai, Puccini, Alberto, Xiu, Joanne, Baca, Yasmine, Spizzo, Gilbert, Lenz, Heinz-Josef, Battaglin, Francesca, Goldberg, Richard M, Grothey, Axel, Shields, Anthony F, Salem, Mohamed E, Marshall, John L, Korn, W Michael, Wolf, Dominik, Kocher, Florian, Seeber, Andreas
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 22.05.2020; MDPI
• Subjects: Adenomatous polyposis coli; BRCAness; Cancer; Cell cycle; Colorectal cancer; Colorectal carcinoma; Deoxyribonucleic acid; DNA; DNA methylation; DNA repair; Genes; Genomic instability; Genomics; Genotype & phenotype; Hybridization; Immune checkpoint; Immunohistochemistry; Medical prognosis; Metastasis; Microsatellite instability; Mismatch repair; Missense mutation; MSI-H/dMMR; Mutation; Next-generation sequencing; p53 Protein; PD-L1; PD-L1 protein; Phenotypes; Proteomics; Studies; TMB; Tumors; Werner's syndrome; WRN; WRN; colorectal cancer; immunotherapy; MSI-H/dMMR; PD-L1; TMB; BRCAness; molecular profiling
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers12051319

Werner syndrome gene ( ) contributes to DNA repair. In cancer, mutations ( -mut) lead to genomic instability. Thus, is a promising target in cancers with microsatellite instability (MSI). We assessed this study to investigate the molecular profile of -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. -mut were detected in 80 of 6854 samples (1.2%). -mut were more prevalent in right-sided compared to left-sided CRC (2.5% vs. 0.7%, < 0.0001). TMB, PD-L1 and MSI-H/dMMR were significantly higher in -mut than in 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 -mut and -wt CRC were observed, i.e., (47% vs. 71%), (34% vs. 49%) and (56% vs. 73%). This is the largest molecular profiling study investigating the genetic landscape of -mut CRCs so far. A high prevalence of MSI-H/dMMR, higher TMB and PD-L1 in -mut tumors were observed. Our data might serve as an additional selection tool for trials testing immune checkpoint antibodies in -mut CRC.