Detection of clinically relevant variants in the TP53 gene below 10% allelic frequency : A multicenter study by ERIC, the European Research Initiative on CLL
Pavlova, Sarka (Masaryk University)
Malcikova, Jitka (Masaryk University)
Radova, Lenka (Masaryk University)
Bonfiglio, Silvia (IRCCS Ospedale San Raffaele (Milà, Itàlia))
Cowland, Jack B. (Copenhagen University Hospital - Rigshospitalet)
Brieghel, Christian (Copenhagen University Hospital - Rigshospitalet)
Andersen, Mette K. (Copenhagen University Hospital - Rigshospitalet)
Karypidou, Maria (Centre for Research and Technology Hellas (Tessalònica, Grècia))
Biderman, Bella (National Medical Research Center for Hematology)
Doubek, Michael (Masaryk University)
Lazarian, Gregory (Université Sorbonne Paris Nord)
Rapado, Inmaculada (Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12))
Vynck, Matthijs (AZ Sint-Jan Hospital)
Porret, Naomi A. (Bern University Hospital)
Andres, Martin (Bern University Hospital)
Rosenberg, Dina (Rambam Medical Center)
Sahar, Dvora (Rambam Medical Center)
Martínez-Laperche, Carolina (Hospital General Universitario Gregorio Marañón)
Buño, Ismael (Universidad Complutense de Madrid)
Hindley, Andrew (Belfast City Hospital (Belfast, Irlanda))
Donaldson, David (Belfast City Hospital (Belfast, Irlanda))
Sánchez, Julio B. (Hospital Universitario Puerta de Hierro Majadahonda (Madrid))
García-Marco, José A. (Hospital Universitario Puerta de Hierro Majadahonda (Madrid))
Serrano-Alcalá, Alicia (Hospital Clínico Universitario-INCLIVA)
Ferrer-Lores, Blanca (Hospital Clínico Universitario-INCLIVA)
Fernandez-Rodríguez, Concepción (Hospital del Mar, IMIM (Hospital del Mar Medical Research Institute))
Bellosillo Paricio, Beatriz (Hospital del Mar, IMIM (Hospital del Mar Medical Research Institute))
Stilgenbauer, Stephan (Ulm University)
Tausch, Eugen (Ulm University)
Nikdin, Hero (Karolinska University Hospital)
Quinn, Fiona (Centre for Laboratory Medicine and Molecular Pathology, St. James Hospital)
Atkinson, Emer (Centre for Laboratory Medicine and Molecular Pathology, St. James Hospital)
van de Corput, Lisette (University Medical Center Utrecht)
Yildiz, Cafer (University Medical Center Utrecht)
Bilbao-Sieyro, Cristina (Hospital Universitario de Gran Canaria Dr. Negrín)
Florido, Yanira (Hospital Universitario de Gran Canaria Dr. Negrín)
Thiede, Christian (AgenDix GmbH)
Schuster, Caroline (AgenDix GmbH)
Stoj, Anastazja (University Hospital in Krakow)
Czekalska, Sylwia (University Hospital in Krakow)
Chatzidimitriou, Anastasia (Centre for Research and Technology Hellas (Tessalònica, Grècia))
Laidou, Stamatia (Centre for Research and Technology Hellas (Tessalònica, Grècia))
Bidet, Audrey (CHU Bordeaux)
Dussiau, Charles (CHU Bordeaux)
Nollet, Friedel (AZ Sint-Jan Hospital)
Piras, Giovanna (Ospedale San Francesco)
Monne, Maria (Ospedale San Francesco)
Smirnova, Svetlana (National Medical Research Center for Hematology)
Nikitin, Eugene (Russian Medical Academy of Continuous Professional Education)
Sloma, Ivan (AP-HP, Hopital Henri Mondor)
Claudel, Alexis (AP-HP, Hopital Henri Mondor)
Largeaud, Laetitia (Institut Universitaire de Cancérologie de Toulouse)
Ysebaert, Loic (Institut Universitaire de Cancérologie de Toulouse)
Valk, Peter J. M. (University Medical Center Rotterdam)
Christian, Amy (University Hospitals Dorset)
Walewska, Renata (University Hospitals Dorset)
Oscier, David (University Hospitals Dorset)
Sebastião, Marta (Instituto Português de Oncologia de Lisboa)
Gomes da Silva, Maria (Instituto Português de Oncologia de Lisboa)
Galieni, Piero (Mazzoni Hospital-Ascoli Piceno)
Angelini, Mario (Mazzoni Hospital-Ascoli Piceno)
Rossi, Davide (Institute of Southern Switzerland)
Spina, Valeria (Ente Ospedaliero Cantonale)
Matos, Sónia (Instituto de Medicina Molecular, Faculdade de Medicina (Lisboa, Portugal))
Martins, Vânia (Instituto de Medicina Molecular, Faculdade de Medicina (Lisboa, Portugal))
Stokłosa, Tomasz (Medical University of Warsaw)
Pepek, Monika (Medical University of Warsaw)
Baliakas, Panagiotis (Uppsala University)
Andreu, Rafa (Hospital Universitari i Politècnic La Fe (València))
Luna, Irene (Hospital Universitari i Politècnic La Fe (València))
Kahre, Tiina (Tartu University)
Murumets, Ülle (Tartu University Hospital (Tartu, Estònia))
Pikousova, Tereza (Masaryk University)
Kurucova, Terezia (Masaryk University)
Laird, Sophie (Salisbury NHS Foundation Trust)
Ward, Daniel (Salisbury NHS Foundation Trust)
Alcoceba, Miguel (Hospital Universitario de Salamanca)
Balanzategui, Ana (Hospital Universitario de Salamanca)
Scarfò, Lydia (Università Vita-Salute San Raffaele)
Gandini, Francesca (Università Vita-Salute San Raffaele)
Zapparoli, Ettore (IRCCS Ospedale San Raffaele (Milà, Itàlia))
Blanco, Adoración (Hospital Universitari Vall d'Hebron)
Abrisqueta, Pau (Universitat Autònoma de Barcelona. Departament de Medicina)
Rodríguez-Vicente, Ana E. (Universidad de Salamanca)
Benito, Rocío (Universidad de Salamanca)
Bravetti, Clotilde (Sorbonne Université, AP-HP, Pitié-Salpêtrière Hospital)
Davi, Frédéric (Sorbonne Université, AP-HP, Pitié-Salpêtrière Hospital)
Gameiro, Paula (Instituto Português de Oncologia de Lisboa)
Martínez-López, Joaquín (Hospital Universitario 12 de Octubre (Madrid))
Tazón-Vega, Bárbara (Hospital Universitari Vall d'Hebron)
Baran-Marszak, Fanny (Université Sorbonne Paris Nord)
Davis, Zadie (University Hospitals Dorset)
Catherwood, Mark (Belfast City Hospital (Belfast, Irlanda))
Sudarikov, Andrey (National Medical Research Center for Hematology)
Rosenquist, Richard (Karolinska University Hospital)
Niemann, Carsten U. (Copenhagen University Hospital - Rigshospitalet)
Stamatopoulos, Kostas (Centre for Research and Technology Hellas (Tessalònica, Grècia))
Ghia, Paolo (Università Vita-Salute San Raffaele)
Pospisilova, Sarka (Masaryk University)

Data:	2025
Resum:	In chronic lymphocytic leukemia, the reliability of next-generation sequencing (NGS) to detect TP53 variants ≤10% allelic frequency (low-VAF) 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-off, respectively. While only one false positive (FP) result was reported at >2% VAF, it was more challenging to distinguish true variants <2% VAF from background noise (37 FPs reported by 9 laboratories). The impact of low-VAF variants on time-to-second-treatment (TTST) and overall survival (OS) was investigated in a series of 1092 patients. Among patients not treated with targeted agents, patients with low-VAF TP53 variants had shorter TTST and OS versus wt- TP53 patients, and the relative risk of second-line treatment or death increased continuously with increasing VAF. Targeted therapy in ≥2 line diminished the difference in OS between patients with low-VAF TP53 variants and wt- TP53 patients, while patients with high-VAF TP53 variants had inferior OS compared to wild type- TP53 cases. Altogether, NGS-based approaches are technically capable of detecting low-VAF variants. No strict threshold can be suggested from a technical standpoint, laboratories reporting TP53 mutations should participate in a standardized validation set-up. Finally, whereas low-VAF 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 TP53 assessment, which is indispensable for elucidating the role of TP53 mutations in targeted treatment.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	HemaSphere, Vol. 9, num. 1, art. 70065 (january 2025) , ISSN 2572-9241

DOI: 10.1002/hem3.70065
PMID: 39840379

13 p, 2.3 MB

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