Detection of clinically relevant variants in the TP53 gene below 10% allelic frequency: A multicenter study by ERIC, the European Research Initiative on CLL
PAVLOVÁ, Šárka, Jitka MALČÍKOVÁ, Lenka RADOVÁ, Silvia BONFIGLIO, Jack B COWLAND et. al.
Detection of clinically relevant variants in the TP53 gene below 10% allelic frequency: A multicenter study by ERIC, the European Research Initiative on CLL
Authors
PAVLOVÁ, Šárka, Jitka MALČÍKOVÁ, Lenka RADOVÁ, Silvia BONFIGLIO, Jack B COWLAND, Christian BRIEGHEL, Mette K ANDERSEN, Maria KARYPIDOU, Bella BIDERMAN, Michael DOUBEK, Gregory LAZARIAN, Inmaculada RAPADO, Matthijs VYNCK, Naomi A PORRET, Martin ANDRES, Dina ROSENBERG, Dvora SAHAR, Carolina MARTINEZ-LAPERCHE, Ismael BUNO, Andrew HINDLEY, David DONALDSON, Julio B SANCHEZ, Jose A GARCIA-MARCO, Alicia SERRANO-ALCALA, Blanca FERRER-LORES, Concepcion FERNANDEZ-RODRIGUEZ, Beatriz BELLOSILLO, Stephan STILGENBAUER, Eugen TAUSCH, Hero NIKDIN, Fiona QUINN, Emer ATKINSON, van de Corput LISETTE, Cafer YILDIZ, Cristina BILBAO-SIEYRO, Yanira FLORIDO, Christian THIEDE, Caroline SCHUSTER, Anastazja STOJ, Sylwia CZEKALSKA, Anastasia CHATZIDIMITRIOU, Stamatia LAIDOU, Audrey BIDET, Charles DUSSIAU, Friedel NOLLET, Giovanna PIRAS, Maria MONNE, Svetlana SMIRNOVA, Eugene NIKITIN, Ivan SLOMA, Alexis CLAUDEL, Laetitia LARGEAUD, Loic YSEBAERT, Peter J M VALK, Amy CHRISTIAN, Renata WALEWSKA, David OSCIER, Marta SEBASTIAO, da Silva Maria GOMES, Piero GALIENI, Mario ANGELINI, Davide ROSSI, Valeria SPINA, Sonia MATOS, Vania MARTINS, Tomasz STOKLOSA, Monika PEPEK, Panagiotis BALIAKAS, Rafa ANDREU, Irene LUNA, Tiina KAHRE, Ulle MURUMETS, Tereza PIKOUSOVA, Terezia KURUCOVA, Sophie LAIRD, Daniel WARD, Miguel ALCOCEBA, Ana BALANZATEGUI, Lydia SCARFO, Francesca GANDINI, Ettore ZAPPAROLI, Adoracion BLANCO, Pau ABRISQUETA, Ana E RODRIGUEZ-VICENTE, Rocio BENITO, Clotilde BRAVETTI, Frederic DAVI, Paula GAMEIRO, Joaquin MARTINEZ-LOPEZ, Barbara TAZON-VEGA, Fanny BARAN-MARSZAK, Zadie DAVIS, Mark CATHERWOOD, Andrey SUDARIKOV, Richard ROSENQUIST, Carsten U NIEMANN, Kostas STAMATOPOULOS, Paolo GHIA and Šárka POSPÍŠILOVÁ
lt;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.
PAVLOVÁ, Šárka, Jitka MALČÍKOVÁ, Lenka RADOVÁ, Silvia BONFIGLIO, Jack B COWLAND, Christian BRIEGHEL, Mette K ANDERSEN, Maria KARYPIDOU, Bella BIDERMAN, Michael DOUBEK, Gregory LAZARIAN, Inmaculada RAPADO, Matthijs VYNCK, Naomi A PORRET, Martin ANDRES, Dina ROSENBERG, Dvora SAHAR, Carolina MARTINEZ-LAPERCHE, Ismael BUNO, Andrew HINDLEY, David DONALDSON, Julio B SANCHEZ, Jose A GARCIA-MARCO, Alicia SERRANO-ALCALA, Blanca FERRER-LORES, Concepcion FERNANDEZ-RODRIGUEZ, Beatriz BELLOSILLO, Stephan STILGENBAUER, Eugen TAUSCH, Hero NIKDIN, Fiona QUINN, Emer ATKINSON, van de Corput LISETTE, Cafer YILDIZ, Cristina BILBAO-SIEYRO, Yanira FLORIDO, Christian THIEDE, Caroline SCHUSTER, Anastazja STOJ, Sylwia CZEKALSKA, Anastasia CHATZIDIMITRIOU, Stamatia LAIDOU, Audrey BIDET, Charles DUSSIAU, Friedel NOLLET, Giovanna PIRAS, Maria MONNE, Svetlana SMIRNOVA, Eugene NIKITIN, Ivan SLOMA, Alexis CLAUDEL, Laetitia LARGEAUD, Loic YSEBAERT, Peter J M VALK, Amy CHRISTIAN, Renata WALEWSKA, David OSCIER, Marta SEBASTIAO, da Silva Maria GOMES, Piero GALIENI, Mario ANGELINI, Davide ROSSI, Valeria SPINA, Sonia MATOS, Vania MARTINS, Tomasz STOKLOSA, Monika PEPEK, Panagiotis BALIAKAS, Rafa ANDREU, Irene LUNA, Tiina KAHRE, Ulle MURUMETS, Tereza PIKOUSOVA, Terezia KURUCOVA, Sophie LAIRD, Daniel WARD, Miguel ALCOCEBA, Ana BALANZATEGUI, Lydia SCARFO, Francesca GANDINI, Ettore ZAPPAROLI, Adoracion BLANCO, Pau ABRISQUETA, Ana E RODRIGUEZ-VICENTE, Rocio BENITO, Clotilde BRAVETTI, Frederic DAVI, Paula GAMEIRO, Joaquin MARTINEZ-LOPEZ, Barbara TAZON-VEGA, Fanny BARAN-MARSZAK, Zadie DAVIS, Mark CATHERWOOD, Andrey SUDARIKOV, Richard ROSENQUIST, Carsten U NIEMANN, Kostas STAMATOPOULOS, Paolo GHIA and Šárka POSPÍŠILOVÁ. Detection of clinically relevant variants in the TP53 gene below 10% allelic frequency: A multicenter study by ERIC, the European Research Initiative on CLL. HemaSphere. Philadelphia: Wilkins, 2025, vol. 9, No 1, p. 1-13. ISSN 2572-9241. Available from: https://dx.doi.org/10.1002/hem3.70065.
@article{70807, author = {Pavlová, Šárka and Malčíková, Jitka and Radová, Lenka and Bonfiglio, Silvia and Cowland, Jack B and Brieghel, Christian and Andersen, Mette K and Karypidou, Maria and Biderman, Bella and Doubek, Michael and Lazarian, Gregory and Rapado, Inmaculada and Vynck, Matthijs and Porret, Naomi A and Andres, Martin and Rosenberg, Dina and Sahar, Dvora and MartinezandLaperche, Carolina and Buno, Ismael and Hindley, Andrew and Donaldson, David and Sanchez, Julio B and GarciaandMarco, Jose A and SerranoandAlcala, Alicia and FerrerandLores, Blanca and FernandezandRodriguez, Concepcion and Bellosillo, Beatriz and Stilgenbauer, Stephan and Tausch, Eugen and Nikdin, Hero and Quinn, Fiona and Atkinson, Emer and Lisette, van de Corput and Yildiz, Cafer and BilbaoandSieyro, Cristina and Florido, Yanira and Thiede, Christian and Schuster, Caroline and Stoj, Anastazja and Czekalska, Sylwia and Chatzidimitriou, Anastasia and Laidou, Stamatia and Bidet, Audrey and Dussiau, Charles and Nollet, Friedel and Piras, Giovanna and Monne, Maria and Smirnova, Svetlana and Nikitin, Eugene and Sloma, Ivan and Claudel, Alexis and Largeaud, Laetitia and Ysebaert, Loic and Valk, Peter J M and Christian, Amy and Walewska, Renata and Oscier, David and Sebastiao, Marta and Gomes, da Silva Maria and Galieni, Piero and Angelini, Mario and Rossi, Davide and Spina, Valeria and Matos, Sonia and Martins, Vania and Stoklosa, Tomasz and Pepek, Monika and Baliakas, Panagiotis and Andreu, Rafa and Luna, Irene and Kahre, Tiina and Murumets, Ulle and Pikousova, Tereza and Kurucova, Terezia and Laird, Sophie and Ward, Daniel and Alcoceba, Miguel and Balanzategui, Ana and Scarfo, Lydia and Gandini, Francesca and Zapparoli, Ettore and Blanco, Adoracion and Abrisqueta, Pau and RodriguezandVicente, Ana E and Benito, Rocio and Bravetti, Clotilde and Davi, Frederic and Gameiro, Paula and MartinezandLopez, Joaquin and TazonandVega, Barbara and BaranandMarszak, Fanny and Davis, Zadie and Catherwood, Mark and Sudarikov, Andrey and Rosenquist, Richard and Niemann, Carsten U and Stamatopoulos, Kostas and Ghia, Paolo and Pospíšilová, Šárka}, article_location = {Philadelphia}, article_number = {1}, doi = {http://dx.doi.org/10.1002/hem3.70065}, keywords = {chronic lymphocytic leukemia; next-generation sequencing; TP53 variants}, language = {eng}, issn = {2572-9241}, journal = {HemaSphere}, title = {Detection of clinically relevant variants in the TP53 gene below 10% allelic frequency: A multicenter study by ERIC, the European Research Initiative on CLL}, url = {https://onlinelibrary.wiley.com/doi/10.1002/hem3.70065}, volume = {9}, year = {2025} }
TY - JOUR ID - 70807 AU - 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 PY - 2025 TI - Detection of clinically relevant variants in the TP53 gene below 10% allelic frequency: A multicenter study by ERIC, the European Research Initiative on CLL JF - HemaSphere VL - 9 IS - 1 SP - 1-13 EP - 1-13 PB - Wilkins SN - 2572-9241 KW - chronic lymphocytic leukemia KW - next-generation sequencing KW - TP53 variants UR - https://onlinelibrary.wiley.com/doi/10.1002/hem3.70065 N2 - lt;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. ER -
PAVLOVÁ, Šárka, Jitka MALČÍKOVÁ, Lenka RADOVÁ, Silvia BONFIGLIO, Jack B COWLAND, Christian BRIEGHEL, Mette K ANDERSEN, Maria KARYPIDOU, Bella BIDERMAN, Michael DOUBEK, Gregory LAZARIAN, Inmaculada RAPADO, Matthijs VYNCK, Naomi A PORRET, Martin ANDRES, Dina ROSENBERG, Dvora SAHAR, Carolina MARTINEZ-LAPERCHE, Ismael BUNO, Andrew HINDLEY, David DONALDSON, Julio B SANCHEZ, Jose A GARCIA-MARCO, Alicia SERRANO-ALCALA, Blanca FERRER-LORES, Concepcion FERNANDEZ-RODRIGUEZ, Beatriz BELLOSILLO, Stephan STILGENBAUER, Eugen TAUSCH, Hero NIKDIN, Fiona QUINN, Emer ATKINSON, van de Corput LISETTE, Cafer YILDIZ, Cristina BILBAO-SIEYRO, Yanira FLORIDO, Christian THIEDE, Caroline SCHUSTER, Anastazja STOJ, Sylwia CZEKALSKA, Anastasia CHATZIDIMITRIOU, Stamatia LAIDOU, Audrey BIDET, Charles DUSSIAU, Friedel NOLLET, Giovanna PIRAS, Maria MONNE, Svetlana SMIRNOVA, Eugene NIKITIN, Ivan SLOMA, Alexis CLAUDEL, Laetitia LARGEAUD, Loic YSEBAERT, Peter J M VALK, Amy CHRISTIAN, Renata WALEWSKA, David OSCIER, Marta SEBASTIAO, da Silva Maria GOMES, Piero GALIENI, Mario ANGELINI, Davide ROSSI, Valeria SPINA, Sonia MATOS, Vania MARTINS, Tomasz STOKLOSA, Monika PEPEK, Panagiotis BALIAKAS, Rafa ANDREU, Irene LUNA, Tiina KAHRE, Ulle MURUMETS, Tereza PIKOUSOVA, Terezia KURUCOVA, Sophie LAIRD, Daniel WARD, Miguel ALCOCEBA, Ana BALANZATEGUI, Lydia SCARFO, Francesca GANDINI, Ettore ZAPPAROLI, Adoracion BLANCO, Pau ABRISQUETA, Ana E RODRIGUEZ-VICENTE, Rocio BENITO, Clotilde BRAVETTI, Frederic DAVI, Paula GAMEIRO, Joaquin MARTINEZ-LOPEZ, Barbara TAZON-VEGA, Fanny BARAN-MARSZAK, Zadie DAVIS, Mark CATHERWOOD, Andrey SUDARIKOV, Richard ROSENQUIST, Carsten U NIEMANN, Kostas STAMATOPOULOS, Paolo GHIA and Šárka POSPÍŠILOVÁ. Detection of clinically relevant variants in the TP53 gene below 10\%{} allelic frequency: A multicenter study by ERIC, the European Research Initiative on CLL. \textit{HemaSphere}. Philadelphia: Wilkins, 2025, vol.~9, No~1, p.~1-13. ISSN~2572-9241. Available from: https://dx.doi.org/10.1002/hem3.70065.
