{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T23:01:06Z","timestamp":1785538866462,"version":"3.56.0"},"reference-count":39,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2020,5,22]],"date-time":"2020-05-22T00:00:00Z","timestamp":1590105600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>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 &lt; 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.<\/jats:p>","DOI":"10.3390\/cancers12051319","type":"journal-article","created":{"date-parts":[[2020,5,22]],"date-time":"2020-05-22T10:18:18Z","timestamp":1590142698000},"page":"1319","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["WRN-Mutated Colorectal Cancer Is Characterized by a Distinct Genetic Phenotype"],"prefix":"10.3390","volume":"12","author":[{"given":"Kai","family":"Zimmer","sequence":"first","affiliation":[{"name":"Department of Hematology and Oncology, Comprehensive Cancer Center Innsbruck, Innsbruck Medical University, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2492-4043","authenticated-orcid":false,"given":"Alberto","family":"Puccini","sequence":"additional","affiliation":[{"name":"Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne","family":"Xiu","sequence":"additional","affiliation":[{"name":"Caris Life Sciences, Phoenix, AZ 85040, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmine","family":"Baca","sequence":"additional","affiliation":[{"name":"Caris Life Sciences, Phoenix, AZ 85040, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilbert","family":"Spizzo","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Comprehensive Cancer Center Innsbruck, Innsbruck Medical University, 6020 Innsbruck, Austria"},{"name":"Department of Internal Medicine, Oncologic Day Hospital, Bressanone Hospital (SABES-ASDAA), 39042 Bressanone-Brixen, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heinz-Josef","family":"Lenz","sequence":"additional","affiliation":[{"name":"Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9869-0163","authenticated-orcid":false,"given":"Francesca","family":"Battaglin","sequence":"additional","affiliation":[{"name":"Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0308-8223","authenticated-orcid":false,"given":"Richard M.","family":"Goldberg","sequence":"additional","affiliation":[{"name":"West Virginia University Cancer Institute, Morgantown, WV 26506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel","family":"Grothey","sequence":"additional","affiliation":[{"name":"West Cancer Center, Germantown, TN 38138, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony F.","family":"Shields","sequence":"additional","affiliation":[{"name":"Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed E.","family":"Salem","sequence":"additional","affiliation":[{"name":"Levine Cancer Institute, Charlotte, NC 28204, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John L.","family":"Marshall","sequence":"additional","affiliation":[{"name":"Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. Michael","family":"Korn","sequence":"additional","affiliation":[{"name":"Caris Life Sciences, Phoenix, AZ 85040, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominik","family":"Wolf","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Comprehensive Cancer Center Innsbruck, Innsbruck Medical University, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Kocher","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Comprehensive Cancer Center Innsbruck, Innsbruck Medical University, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8529-7824","authenticated-orcid":false,"given":"Andreas","family":"Seeber","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Comprehensive Cancer Center Innsbruck, Innsbruck Medical University, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1568","DOI":"10.1200\/JCO.2018.36.15_suppl.1568","article-title":"Global Burden of Disease Cancer Collaboration Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 2006 to 2016: A systematic analysis for the Global Burden of Disease study","volume":"36","author":"Fitzmaurice","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.1016\/S1470-2045(18)30700-9","article-title":"Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial","volume":"19","author":"Hodi","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2518","DOI":"10.1200\/JCO.19.00934","article-title":"Five-Year Overall Survival for Patients With Advanced Non\u2012Small-Cell Lung Cancer Treated With Pembrolizumab: Results From the Phase I KEYNOTE-001 Study","volume":"37","author":"Garon","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1056\/NEJMoa1500596","article-title":"PD-1 Blockade in Tumors with Mismatch-Repair Deficiency","volume":"372","author":"Le","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/s41575-019-0126-x","article-title":"Immunotherapy in colorectal cancer: Rationale, challenges and potential","volume":"16","author":"Ganesh","year":"2019","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5322","DOI":"10.1158\/1078-0432.CCR-14-0332","article-title":"Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: A pooled analysis of the CAIRO, CAIRO2, COIN and FOCUS studies","volume":"20","author":"Venderbosch","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2073","DOI":"10.1053\/j.gastro.2009.12.064","article-title":"Microsatellite instability in colorectal cancer","volume":"138","author":"Boland","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1038\/sj.bjc.6604867","article-title":"Deficient mismatch repair system in patients with sporadic advanced colorectal cancer","volume":"100","author":"Koopman","year":"2009","journal-title":"Br. J. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1158\/1078-0432.CCR-15-1678","article-title":"Microsatellite Instability as a Biomarker for PD-1 Blockade","volume":"22","author":"Dudley","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1038\/nm.3967","article-title":"The consensus molecular subtypes of colorectal cancer","volume":"21","author":"Guinney","year":"2015","journal-title":"Nat. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1038\/s41586-019-1102-x","article-title":"WRN helicase is a synthetic lethal target in microsatellite unstable cancers","volume":"568","author":"Chan","year":"2019","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1038\/s41586-019-1103-9","article-title":"Prioritization of cancer therapeutic targets using CRISPR\u2013Cas9 screens","volume":"568","author":"Behan","year":"2019","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Lauper, J.M., Krause, A., Vaughan, T.L., and Monnat, R.J. (2013). Spectrum and Risk of Neoplasia in Werner Syndrome: A Systematic Review. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0059709"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.arr.2016.03.002","article-title":"Werner syndrome: Clinical features, pathogenesis and potential therapeutic interventions","volume":"33","author":"Oshima","year":"2016","journal-title":"Ageing Res. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.jss.2012.10.790","article-title":"Altered RecQ Helicase Expression in Sporadic Primary Colorectal Cancers","volume":"179","author":"Lao","year":"2013","journal-title":"J. Surg. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1136\/gutjnl-2011-300865","article-title":"Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum","volume":"61","author":"Yamauchi","year":"2012","journal-title":"Gut"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"264","DOI":"10.14740\/gr1062w","article-title":"Difference Between Left-Sided and Right-Sided Colorectal Cancer: A Focused Review of Literature","volume":"11","author":"Baran","year":"2018","journal-title":"Gastroenterol. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.1053\/j.gastro.2009.12.065","article-title":"The chromosomal instability pathway in colon cancer","volume":"138","author":"Pino","year":"2010","journal-title":"Gastroenterol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/0092-8674(90)90186-I","article-title":"A genetic model for colorectal tumorigenesis","volume":"61","author":"Fearon","year":"1990","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1038\/nrc.2015.21","article-title":"BRCAness revisited","volume":"16","author":"Lord","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1200\/PO.17.00286","article-title":"Prevalence of Homologous Recombination\u2013Related Gene Mutations Across Multiple Cancer Types","volume":"2018","author":"Heeke","year":"2018","journal-title":"JCO Precis. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1056\/NEJMoa1903387","article-title":"Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer","volume":"381","author":"Golan","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1056\/NEJMoa1706450","article-title":"Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation","volume":"377","author":"Robson","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1634\/theoncologist.2015-0319","article-title":"Phase II Study of Olaparib (AZD-2281) After Standard Systemic Therapies for Disseminated Colorectal Cancer","volume":"21","author":"Leichman","year":"2016","journal-title":"Oncologist"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1007\/s10637-016-0351-x","article-title":"A Phase I study of olaparib and irinotecan in patients with colorectal cancer: Canadian Cancer Trials Group IND 187","volume":"34","author":"Chen","year":"2016","journal-title":"Investig. New Drugs"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1038\/modpathol.3800996","article-title":"WRN promoter methylation possibly connects mucinous differentiation, microsatellite instability and CpG island methylator phenotype in colorectal cancer","volume":"21","author":"Kawasaki","year":"2007","journal-title":"Mod. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.ejca.2018.11.002","article-title":"Predictive biomarkers of response for immune checkpoint inhibitors in non-small-cell lung cancer","volume":"106","author":"Prelaj","year":"2018","journal-title":"Eur. J. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2598","DOI":"10.1158\/1535-7163.MCT-17-0386","article-title":"Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers","volume":"16","author":"Goodman","year":"2017","journal-title":"Mol. Cancer Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1093\/annonc\/mdz134","article-title":"Tumor mutational burden is predictive of response to immune checkpoint inhibitors in MSI-high metastatic colorectal cancer","volume":"30","author":"Schrock","year":"2019","journal-title":"Ann. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1146\/annurev-biochem-060713-035428","article-title":"Human RecQ helicases in DNA repair, recombination, and replication","volume":"83","author":"Croteau","year":"2014","journal-title":"Annu. Rev. Biochem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e542","DOI":"10.1016\/S1470-2045(16)30406-5","article-title":"Predictive biomarkers for checkpoint inhibitor-based immunotherapy","volume":"17","author":"Gibney","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1016\/S1470-2045(17)30422-9","article-title":"Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): An open-label, multicentre, phase 2 study","volume":"18","author":"Overman","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1038\/ng.3127","article-title":"RNF43 is frequently mutated in colorectal and endometrial cancers","volume":"46","author":"Giannakis","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3588","DOI":"10.1200\/JCO.2019.37.15_suppl.3588","article-title":"Molecular landscape of colorectal cancers harboring R-spondin fusions","volume":"37","author":"Seeber","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1073\/pnas.1006423108","article-title":"Inhibition of helicase activity by a small molecule impairs Werner syndrome helicase (WRN) function in the cellular response to DNA damage or replication stress","volume":"108","author":"Aggarwal","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3329","DOI":"10.4161\/cc.26320","article-title":"Targeting an Achilles\u2019 heel of cancer with a WRN helicase inhibitor. Function of a membrane-embedded domain evolutionarily multiplied in the GPI lipid anchor pathway proteins PIG-B, PIG-M, PIG-U, PIG-W, PIG-V, and PIG-Z","volume":"12","author":"Aggarwal","year":"2013","journal-title":"Cell Cycle"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.chembiol.2012.10.016","article-title":"A small molecule inhibitor of the BLM helicase modulates chromosome stability in human cells","volume":"20","author":"Nguyen","year":"2013","journal-title":"Chem. Boil."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Sommers, J.A., Kulikowicz, T., Croteau, D.L., Dexheimer, T., Dorjsuren, D., Jadhav, A., Maloney, D.J., Simeonov, A., Bohr, V.A., and Brosh, R.M. (2019). A high-throughput screen to identify novel small molecule inhibitors of the Werner Syndrome Helicase-Nuclease (WRN). PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0210525"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"59","DOI":"10.3389\/fmolb.2018.00059","article-title":"New Insights Into DNA Helicases as Druggable Targets for Cancer Therapy","volume":"5","author":"Datta","year":"2018","journal-title":"Front. Mol. Biosci."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/5\/1319\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:31:24Z","timestamp":1760175084000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/5\/1319"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,22]]},"references-count":39,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2020,5]]}},"alternative-id":["cancers12051319"],"URL":"https:\/\/doi.org\/10.3390\/cancers12051319","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,22]]}}}