{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T21:50:44Z","timestamp":1789595444259,"version":"build-2803163510"},"reference-count":51,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,1,20]],"date-time":"2025-01-20T00:00:00Z","timestamp":1737331200000},"content-version":"vor","delay-in-days":19,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013209","name":"Hellenic Foundation for Research and Innovation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013209","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["21198"],"award-info":[{"award-number":["21198"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["HemaSphere"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In chronic lymphocytic leukemia, the reliability of next\u2010generation sequencing (NGS) to detect <jats:italic>TP53<\/jats:italic> variants \u226410% allelic frequency (low\u2010VAF) is debated. We tested the ability to detect 23 such variants in 41 different laboratories using their NGS method of choice. The sensitivity was 85.6%, 94.5%, and 94.8% at 1%, 2%, and 3% VAF cut\u2010off, respectively. While only one false positive (FP) result was reported at &gt;2% VAF, it was more challenging to distinguish true variants &lt;2% VAF from background noise (37 FPs reported by 9 laboratories). The impact of low\u2010VAF variants on time\u2010to\u2010second\u2010treatment (TTST) and overall survival (OS) was investigated in a series of 1092 patients. Among patients not treated with targeted agents, patients with low\u2010VAF <jats:italic>TP53<\/jats:italic> variants had shorter TTST and OS versus wt\u2010<jats:italic>TP53<\/jats:italic> patients, and the relative risk of second\u2010line treatment or death increased continuously with increasing VAF. Targeted therapy in \u22652 line diminished the difference in OS between patients with low\u2010VAF <jats:italic>TP53<\/jats:italic> variants and wt\u2010<jats:italic>TP53<\/jats:italic> patients, while patients with high\u2010VAF <jats:italic>TP53<\/jats:italic> variants had inferior OS compared to wild type\u2010<jats:italic>TP53<\/jats:italic> cases. Altogether, NGS\u2010based approaches are technically capable of detecting low\u2010VAF variants. No strict threshold can be suggested from a technical standpoint, laboratories reporting <jats:italic>TP53<\/jats:italic> mutations should participate in a standardized validation set\u2010up. Finally, whereas low\u2010VAF variants affected outcomes in patients receiving chemoimmunotherapy, their impact on those treated with novel therapies remains undetermined. Our results pave the way for the harmonized and accurate <jats:italic>TP53<\/jats:italic> assessment, which is indispensable for elucidating the role of <jats:italic>TP53<\/jats:italic> mutations in targeted treatment.<\/jats:p>","DOI":"10.1002\/hem3.70065","type":"journal-article","created":{"date-parts":[[2025,1,21]],"date-time":"2025-01-21T07:24:06Z","timestamp":1737444246000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Detection of clinically relevant variants in the <i>TP53<\/i> gene below 10% allelic frequency: A multicenter study by ERIC, the European Research Initiative on CLL"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1528-9743","authenticated-orcid":false,"given":"Sarka","family":"Pavlova","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Hematology and Oncology, and Institute of Medical Genetics and Genomics, University Hospital Brno and Medical Faculty Masaryk University Brno Czech Republic"},{"name":"Centre for Molecular Medicine, Central European Institute of Technology (CEITEC) Masaryk University Brno Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3650-6698","authenticated-orcid":false,"given":"Jitka","family":"Malcikova","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Hematology and Oncology, and Institute of Medical Genetics and Genomics, University Hospital Brno and Medical Faculty Masaryk University Brno Czech Republic"},{"name":"Centre for Molecular Medicine, Central European Institute of Technology (CEITEC) Masaryk University Brno Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8103-148X","authenticated-orcid":false,"given":"Lenka","family":"Radova","sequence":"additional","affiliation":[{"name":"Centre for Molecular Medicine, Central European Institute of Technology (CEITEC) Masaryk University Brno Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Bonfiglio","sequence":"additional","affiliation":[{"name":"B\u2010Cell Neoplasia Unit and Strategic Research Program on CLL IRCCS Ospedale San Raffaele Milan Italy"},{"name":"Center for Omics Sciences IRCCS Ospedale San Raffaele Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack B.","family":"Cowland","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Centre of Diagnostic Investigations Copenhagen University Hospital \u2010 Rigshospitalet Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Brieghel","sequence":"additional","affiliation":[{"name":"Department of Hematology Copenhagen University Hospital \u2010 Rigshospitalet Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mette 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