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

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). T...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281075/
https://www.ncbi.nlm.nih.gov/pubmed/32455893
http://dx.doi.org/10.3390/cancers12051319
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author 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
author_facet 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
author_sort Zimmer, Kai
collection PubMed
description 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.
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spelling pubmed-72810752020-06-15 WRN-Mutated Colorectal Cancer Is Characterized by a Distinct Genetic Phenotype 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 Cancers (Basel) Article 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. MDPI 2020-05-22 /pmc/articles/PMC7281075/ /pubmed/32455893 http://dx.doi.org/10.3390/cancers12051319 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
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
WRN-Mutated Colorectal Cancer Is Characterized by a Distinct Genetic Phenotype
title WRN-Mutated Colorectal Cancer Is Characterized by a Distinct Genetic Phenotype
title_full WRN-Mutated Colorectal Cancer Is Characterized by a Distinct Genetic Phenotype
title_fullStr WRN-Mutated Colorectal Cancer Is Characterized by a Distinct Genetic Phenotype
title_full_unstemmed WRN-Mutated Colorectal Cancer Is Characterized by a Distinct Genetic Phenotype
title_short WRN-Mutated Colorectal Cancer Is Characterized by a Distinct Genetic Phenotype
title_sort wrn-mutated colorectal cancer is characterized by a distinct genetic phenotype
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281075/
https://www.ncbi.nlm.nih.gov/pubmed/32455893
http://dx.doi.org/10.3390/cancers12051319
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