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Article

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

1
Department of Hematology and Oncology, Comprehensive Cancer Center Innsbruck, Innsbruck Medical University, 6020 Innsbruck, Austria
2
Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
3
Caris Life Sciences, Phoenix, AZ 85040, USA
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Department of Internal Medicine, Oncologic Day Hospital, Bressanone Hospital (SABES-ASDAA), 39042 Bressanone-Brixen, Italy
5
West Virginia University Cancer Institute, Morgantown, WV 26506, USA
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West Cancer Center, Germantown, TN 38138, USA
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Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA
8
Levine Cancer Institute, Charlotte, NC 28204, USA
9
Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(5), 1319; https://doi.org/10.3390/cancers12051319
Received: 20 March 2020 / Revised: 14 May 2020 / Accepted: 19 May 2020 / Published: 22 May 2020
(This article belongs to the Special Issue Cancer Biomarkers)
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. View Full-Text
Keywords: WRN; colorectal cancer; MSI-H/dMMR; TMB; PD-L1; BRCAness; molecular profiling; immunotherapy WRN; colorectal cancer; MSI-H/dMMR; TMB; PD-L1; BRCAness; molecular profiling; immunotherapy
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MDPI and ACS Style

Zimmer, K.; Puccini, A.; Xiu, J.; Baca, Y.; Spizzo, G.; Lenz, H.-J.; Battaglin, F.; Goldberg, R.M.; Grothey, A.; Shields, A.F.; Salem, M.E.; Marshall, J.L.; Korn, W.M.; Wolf, D.; Kocher, F.; Seeber, A. WRN-Mutated Colorectal Cancer Is Characterized by a Distinct Genetic Phenotype. Cancers 2020, 12, 1319. https://doi.org/10.3390/cancers12051319

AMA Style

Zimmer K, Puccini A, Xiu J, Baca Y, Spizzo G, Lenz H-J, Battaglin F, Goldberg RM, Grothey A, Shields AF, Salem ME, Marshall JL, Korn WM, Wolf D, Kocher F, Seeber A. WRN-Mutated Colorectal Cancer Is Characterized by a Distinct Genetic Phenotype. Cancers. 2020; 12(5):1319. https://doi.org/10.3390/cancers12051319

Chicago/Turabian Style

Zimmer, Kai, Alberto Puccini, Joanne Xiu, Yasmine Baca, Gilbert Spizzo, Heinz-Josef Lenz, Francesca Battaglin, Richard M. Goldberg, Axel Grothey, Anthony F. Shields, Mohamed E. Salem, John L. Marshall, W. Michael Korn, Dominik Wolf, Florian Kocher, and Andreas Seeber. 2020. "WRN-Mutated Colorectal Cancer Is Characterized by a Distinct Genetic Phenotype" Cancers 12, no. 5: 1319. https://doi.org/10.3390/cancers12051319

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