Subclonal TP53 and KRAS variants combined with poor treatment response identify ultrahigh-risk pediatric patients with T-ALL
Abstract: Variations in the TP53 and KRAS genes indicate a particularly adverse prognosis in relapsed pediatric T-cell acute lymphoblastic leukemia (T-ALL). We hypothesized that these variations might be subclonally present at disease onset and contribute to relapse risk. To test this, we examined 2...
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Elsevier
2025-03-01
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| Series: | Blood Advances |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2473952925000151 |
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| author | Tamara Kempter Paulina Richter-Pechańska Katarzyna Michel Tobias Rausch Büşra Erarslan-Uysal Cornelia Eckert Martin Zimmermann Martin Stanulla Martin Schrappe Gunnar Cario Stefan Köhrer Andishe Attarbaschi Jan O. Korbel Joachim B. Kunz Andreas E. Kulozik |
| author_facet | Tamara Kempter Paulina Richter-Pechańska Katarzyna Michel Tobias Rausch Büşra Erarslan-Uysal Cornelia Eckert Martin Zimmermann Martin Stanulla Martin Schrappe Gunnar Cario Stefan Köhrer Andishe Attarbaschi Jan O. Korbel Joachim B. Kunz Andreas E. Kulozik |
| author_sort | Tamara Kempter |
| collection | DOAJ |
| description | Abstract: Variations in the TP53 and KRAS genes indicate a particularly adverse prognosis in relapsed pediatric T-cell acute lymphoblastic leukemia (T-ALL). We hypothesized that these variations might be subclonally present at disease onset and contribute to relapse risk. To test this, we examined 2 cohorts of children diagnosed with T-ALL: cohort 1 with 81 patients who relapsed and 79 who matched nonrelapsing controls, and cohort 2 with 226 consecutive patients, 30 of whom relapsed. In cohort 1, targeted sequencing revealed TP53 clonal and subclonal variants in 6 of 81 relapsing patients but none in the nonrelapsing group (P = .014). KRAS alterations were found in 9 of 81 relapsing patients compared with 2 of 79 nonrelapsing patients (P = .032). Survival analysis showed that none of the relapsed patients with TP53 and/or KRAS alterations survived, whereas 19 of 67 relapsed patients without such variants did, with a minimum follow-up time of 3 years (P = .023). In cohort 2, none of the relapsing patients but 10 of 196 nonrelapsing patients carried TP53 or KRAS variants, indicating that mutation status alone does not predict poor prognosis. All 10 nonrelapsing patients with mutations had a favorable early treatment response. Among the total cohort of 386 patients, 188 showed poor treatment response, of whom 69 relapsed. Of these poor responders, 9 harbored TP53 or KRAS variants. In conclusion, subclonal TP53 and KRAS alterations identified at the time of initial diagnosis, along with a poor treatment response, characterize a subset of children with T-ALL who face a dismal prognosis and who may benefit from alternative treatment approaches. |
| format | Article |
| id | doaj-art-926fbc018ab84c44ab4d39eb6cda033b |
| institution | OA Journals |
| issn | 2473-9529 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Blood Advances |
| spelling | doaj-art-926fbc018ab84c44ab4d39eb6cda033b2025-08-20T01:58:28ZengElsevierBlood Advances2473-95292025-03-01961267127910.1182/bloodadvances.2024014209Subclonal TP53 and KRAS variants combined with poor treatment response identify ultrahigh-risk pediatric patients with T-ALLTamara Kempter0Paulina Richter-Pechańska1Katarzyna Michel2Tobias Rausch3Büşra Erarslan-Uysal4Cornelia Eckert5Martin Zimmermann6Martin Stanulla7Martin Schrappe8Gunnar Cario9Stefan Köhrer10Andishe Attarbaschi11Jan O. Korbel12Joachim B. Kunz13Andreas E. Kulozik14Department of Pediatric Oncology, Hematology, and Immunology and Hopp Children’s Cancer Center Heidelberg, University of Heidelberg, Heidelberg, Germany; Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, GermanyDepartment of Pediatric Oncology, Hematology, and Immunology and Hopp Children’s Cancer Center Heidelberg, University of Heidelberg, Heidelberg, Germany; Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, GermanyDepartment of Pediatric Oncology, Hematology, and Immunology and Hopp Children’s Cancer Center Heidelberg, University of Heidelberg, Heidelberg, GermanyMolecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany; Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, GermanyDepartment of Pediatric Oncology, Hematology, and Immunology and Hopp Children’s Cancer Center Heidelberg, University of Heidelberg, Heidelberg, Germany; Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, GermanyDepartment of Pediatric Oncology/Hematology, Charité University School of Medicine Berlin, Berlin, GermanyPediatric Hematology and Oncology, Hannover Medical School, Hannover, GermanyPediatric Hematology and Oncology, Hannover Medical School, Hannover, GermanyDepartment of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, GermanyDepartment of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, GermanyLabdia Labordiagnostik, Vienna, Austria; St. Anna Children’s Cancer Research Institute, Vienna, AustriaSt. Anna Children’s Cancer Research Institute, Vienna, Austria; Department of Pediatric Hematology and Oncology, St. Anna Children’s Hospital, Medical University of Vienna, Vienna, AustriaMolecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany; Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany; Bridging Research Division on Mechanisms of Genomic Variation and Data Science, German Cancer Research Center, Heidelberg, GermanyDepartment of Pediatric Oncology, Hematology, and Immunology and Hopp Children’s Cancer Center Heidelberg, University of Heidelberg, Heidelberg, Germany; Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, GermanyDepartment of Pediatric Oncology, Hematology, and Immunology and Hopp Children’s Cancer Center Heidelberg, University of Heidelberg, Heidelberg, Germany; Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Pediatric Leukemia, German Cancer Research Center, Heidelberg, Germany; Correspondence: Andreas E. Kulozik, Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg N/A 69120, Germany;Abstract: Variations in the TP53 and KRAS genes indicate a particularly adverse prognosis in relapsed pediatric T-cell acute lymphoblastic leukemia (T-ALL). We hypothesized that these variations might be subclonally present at disease onset and contribute to relapse risk. To test this, we examined 2 cohorts of children diagnosed with T-ALL: cohort 1 with 81 patients who relapsed and 79 who matched nonrelapsing controls, and cohort 2 with 226 consecutive patients, 30 of whom relapsed. In cohort 1, targeted sequencing revealed TP53 clonal and subclonal variants in 6 of 81 relapsing patients but none in the nonrelapsing group (P = .014). KRAS alterations were found in 9 of 81 relapsing patients compared with 2 of 79 nonrelapsing patients (P = .032). Survival analysis showed that none of the relapsed patients with TP53 and/or KRAS alterations survived, whereas 19 of 67 relapsed patients without such variants did, with a minimum follow-up time of 3 years (P = .023). In cohort 2, none of the relapsing patients but 10 of 196 nonrelapsing patients carried TP53 or KRAS variants, indicating that mutation status alone does not predict poor prognosis. All 10 nonrelapsing patients with mutations had a favorable early treatment response. Among the total cohort of 386 patients, 188 showed poor treatment response, of whom 69 relapsed. Of these poor responders, 9 harbored TP53 or KRAS variants. In conclusion, subclonal TP53 and KRAS alterations identified at the time of initial diagnosis, along with a poor treatment response, characterize a subset of children with T-ALL who face a dismal prognosis and who may benefit from alternative treatment approaches.http://www.sciencedirect.com/science/article/pii/S2473952925000151 |
| spellingShingle | Tamara Kempter Paulina Richter-Pechańska Katarzyna Michel Tobias Rausch Büşra Erarslan-Uysal Cornelia Eckert Martin Zimmermann Martin Stanulla Martin Schrappe Gunnar Cario Stefan Köhrer Andishe Attarbaschi Jan O. Korbel Joachim B. Kunz Andreas E. Kulozik Subclonal TP53 and KRAS variants combined with poor treatment response identify ultrahigh-risk pediatric patients with T-ALL Blood Advances |
| title | Subclonal TP53 and KRAS variants combined with poor treatment response identify ultrahigh-risk pediatric patients with T-ALL |
| title_full | Subclonal TP53 and KRAS variants combined with poor treatment response identify ultrahigh-risk pediatric patients with T-ALL |
| title_fullStr | Subclonal TP53 and KRAS variants combined with poor treatment response identify ultrahigh-risk pediatric patients with T-ALL |
| title_full_unstemmed | Subclonal TP53 and KRAS variants combined with poor treatment response identify ultrahigh-risk pediatric patients with T-ALL |
| title_short | Subclonal TP53 and KRAS variants combined with poor treatment response identify ultrahigh-risk pediatric patients with T-ALL |
| title_sort | subclonal tp53 and kras variants combined with poor treatment response identify ultrahigh risk pediatric patients with t all |
| url | http://www.sciencedirect.com/science/article/pii/S2473952925000151 |
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