Detection of clinically relevant variants in the TP53 gene below 10% allelic frequency: A multicenter study by ERIC, the European Research Initiative on CLL

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Authors

PAVLOVÁ Šárka MALČÍKOVÁ Jitka RADOVÁ Lenka BONFIGLIO Silvia COWLAND Jack B BRIEGHEL Christian ANDERSEN Mette K KARYPIDOU Maria BIDERMAN Bella DOUBEK Michael LAZARIAN Gregory RAPADO Inmaculada VYNCK Matthijs PORRET Naomi A ANDRES Martin ROSENBERG Dina SAHAR Dvora MARTINEZ-LAPERCHE Carolina BUNO Ismael HINDLEY Andrew DONALDSON David SANCHEZ Julio B GARCIA-MARCO Jose A SERRANO-ALCALA Alicia FERRER-LORES Blanca FERNANDEZ-RODRIGUEZ Concepcion BELLOSILLO Beatriz STILGENBAUER Stephan TAUSCH Eugen NIKDIN Hero QUINN Fiona ATKINSON Emer LISETTE van de Corput YILDIZ Cafer BILBAO-SIEYRO Cristina FLORIDO Yanira THIEDE Christian SCHUSTER Caroline STOJ Anastazja CZEKALSKA Sylwia CHATZIDIMITRIOU Anastasia LAIDOU Stamatia BIDET Audrey DUSSIAU Charles NOLLET Friedel PIRAS Giovanna MONNE Maria SMIRNOVA Svetlana NIKITIN Eugene SLOMA Ivan CLAUDEL Alexis LARGEAUD Laetitia YSEBAERT Loic VALK Peter J M CHRISTIAN Amy WALEWSKA Renata OSCIER David SEBASTIAO Marta GOMES da Silva Maria GALIENI Piero ANGELINI Mario ROSSI Davide SPINA Valeria MATOS Sonia MARTINS Vania STOKLOSA Tomasz PEPEK Monika BALIAKAS Panagiotis ANDREU Rafa LUNA Irene KAHRE Tiina MURUMETS Ulle PIKOUSOVA Tereza KURUCOVA Terezia LAIRD Sophie WARD Daniel ALCOCEBA Miguel BALANZATEGUI Ana SCARFO Lydia GANDINI Francesca ZAPPAROLI Ettore BLANCO Adoracion ABRISQUETA Pau RODRIGUEZ-VICENTE Ana E BENITO Rocio BRAVETTI Clotilde DAVI Frederic GAMEIRO Paula MARTINEZ-LOPEZ Joaquin TAZON-VEGA Barbara BARAN-MARSZAK Fanny DAVIS Zadie CATHERWOOD Mark SUDARIKOV Andrey ROSENQUIST Richard NIEMANN Carsten U STAMATOPOULOS Kostas GHIA Paolo POSPÍŠILOVÁ Šárka

Year of publication 2025
Type Article in Periodical
Magazine / Source HemaSphere
MU Faculty or unit

Faculty of Medicine

Citation
web https://onlinelibrary.wiley.com/doi/10.1002/hem3.70065
Doi http://dx.doi.org/10.1002/hem3.70065
Keywords chronic lymphocytic leukemia; next-generation sequencing; TP53 variants
Attached files
Description 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.
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