Design of a targeted next‐generation DNA sequencing panel for pediatric T‐cell lymphoblastic lymphoma to unravel biology and optimize treatment

Low incidence and molecular heterogeneity of pediatric T‐cell lymphoblastic lymphoma (T‐LBL) require an international, large‐scale effort to identify novel clinical biomarkers. The ongoing international clinical trial LBL2018 (NCT04043494) represents an ideal opportunity to implement a common analyt...

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Published in:Genes chromosomes & cancer Vol. 61; no. 8; pp. 459 - 470
Main Authors: Ruether, Charlotte, Wuensch, Christian, Randau, Gerrit, Michgehl, Ulf, Trautmann, Marcel, Hartmann, Wolfgang, Sandmann, Sarah, Dugas, Martin, Khanam, Tasneem, Burkhardt, Birgit
Format: Journal Article
Language:English
Published: Hoboken, USA John Wiley & Sons, Inc 01.08.2022
Wiley Subscription Services, Inc
Subjects:
1-Phosphatidylinositol 3-kinase
AKT protein
Biology
Cell cycle
Child
clinical trials
Deoxyribonucleic acid
DNA
DNA repair
DNA sequencing
Epigenesis, Genetic
Epigenetics
Gene regulation
Genes
High-Throughput Nucleotide Sequencing
Humans
lymphoblastic lymphoma
Lymphoma
Lymphoma, T-Cell - genetics
Mutation
Neoplasm Recurrence, Local - genetics
pediatric oncology
Pediatrics
Phosphatidylinositol 3-Kinases - genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics
Proto-Oncogene Proteins c-akt - genetics
Sequence Analysis, DNA
T-Lymphocytes
targeted gene panel
variant classification
variant classification
clinical trials
targeted gene panel
pediatric oncology
lymphoblastic lymphoma
ISSN:1045-2257, 1098-2264, 1098-2264
Online Access:Get full text
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Abstract Low incidence and molecular heterogeneity of pediatric T‐cell lymphoblastic lymphoma (T‐LBL) require an international, large‐scale effort to identify novel clinical biomarkers. The ongoing international clinical trial LBL2018 (NCT04043494) represents an ideal opportunity to implement a common analytic approach. Targeted next‐generation sequencing is well‐suited for this purpose; however, selection of relevant target genes for T‐LBL remains subject of ongoing debates. Our group has recently designed and evaluated a first target panel of 80 candidate genes for T‐LBL. The present study aimed at developing a novel optimized gene panel for large‐scale application and to promote an international agreement on a common core panel. Small sequence variants obtained from our former study were systematically analyzed and classified with regards to pathogenic relevance, to prioritize candidate genes. Additional genes were curated from literature and online databases for a more comprehensive analysis of relevant functions and signaling pathways. The new target panel TGP‐T‐LBL entails 84 candidate genes which are key actors in NOTCH, PI3K‐AKT, JAK–STAT, RAS signaling, epigenetic regulation, transcription, DNA repair, cell cycle regulation, and ribosomal function. From our former gene panel, 35 out of 80 candidate genes were selected for the novel panel. Forty‐six out of 84 genes are currently being analyzed in the ongoing international trial LBL2018. Exploratory analysis of prognostic relevance on mutation‐level suggested a potential association of PIK3CA variants c.1624G>A(p.Glu542Lys) and c.1633G>A(p.Glu545Lys) to occurrence of relapse, emphasizing particular relevance of mutation analysis in PI3K‐AKT signaling. Our approach promotes comprehensive and clinically relevant mutational profiling of pediatric T‐LBL.
AbstractList Low incidence and molecular heterogeneity of pediatric T‐cell lymphoblastic lymphoma (T‐LBL) require an international, large‐scale effort to identify novel clinical biomarkers. The ongoing international clinical trial LBL2018 (NCT04043494) represents an ideal opportunity to implement a common analytic approach. Targeted next‐generation sequencing is well‐suited for this purpose; however, selection of relevant target genes for T‐LBL remains subject of ongoing debates. Our group has recently designed and evaluated a first target panel of 80 candidate genes for T‐LBL. The present study aimed at developing a novel optimized gene panel for large‐scale application and to promote an international agreement on a common core panel. Small sequence variants obtained from our former study were systematically analyzed and classified with regards to pathogenic relevance, to prioritize candidate genes. Additional genes were curated from literature and online databases for a more comprehensive analysis of relevant functions and signaling pathways. The new target panel TGP‐T‐LBL entails 84 candidate genes which are key actors in NOTCH, PI3K‐AKT, JAK–STAT, RAS signaling, epigenetic regulation, transcription, DNA repair, cell cycle regulation, and ribosomal function. From our former gene panel, 35 out of 80 candidate genes were selected for the novel panel. Forty‐six out of 84 genes are currently being analyzed in the ongoing international trial LBL2018. Exploratory analysis of prognostic relevance on mutation‐level suggested a potential association of PIK3CA variants c.1624G>A(p.Glu542Lys) and c.1633G>A(p.Glu545Lys) to occurrence of relapse, emphasizing particular relevance of mutation analysis in PI3K‐AKT signaling. Our approach promotes comprehensive and clinically relevant mutational profiling of pediatric T‐LBL.
Low incidence and molecular heterogeneity of pediatric T‐cell lymphoblastic lymphoma (T‐LBL) require an international, large‐scale effort to identify novel clinical biomarkers. The ongoing international clinical trial LBL2018 (NCT04043494) represents an ideal opportunity to implement a common analytic approach. Targeted next‐generation sequencing is well‐suited for this purpose; however, selection of relevant target genes for T‐LBL remains subject of ongoing debates. Our group has recently designed and evaluated a first target panel of 80 candidate genes for T‐LBL. The present study aimed at developing a novel optimized gene panel for large‐scale application and to promote an international agreement on a common core panel. Small sequence variants obtained from our former study were systematically analyzed and classified with regards to pathogenic relevance, to prioritize candidate genes. Additional genes were curated from literature and online databases for a more comprehensive analysis of relevant functions and signaling pathways. The new target panel TGP‐T‐LBL entails 84 candidate genes which are key actors in NOTCH, PI3K‐AKT, JAK–STAT, RAS signaling, epigenetic regulation, transcription, DNA repair, cell cycle regulation, and ribosomal function. From our former gene panel, 35 out of 80 candidate genes were selected for the novel panel. Forty‐six out of 84 genes are currently being analyzed in the ongoing international trial LBL2018. Exploratory analysis of prognostic relevance on mutation‐level suggested a potential association of PIK3CA variants c.1624G>A(p.Glu542Lys) and c.1633G>A(p.Glu545Lys) to occurrence of relapse, emphasizing particular relevance of mutation analysis in PI3K‐AKT signaling. Our approach promotes comprehensive and clinically relevant mutational profiling of pediatric T‐LBL.
Low incidence and molecular heterogeneity of pediatric T-cell lymphoblastic lymphoma (T-LBL) require an international, large-scale effort to identify novel clinical biomarkers. The ongoing international clinical trial LBL2018 (NCT04043494) represents an ideal opportunity to implement a common analytic approach. Targeted next-generation sequencing is well-suited for this purpose; however, selection of relevant target genes for T-LBL remains subject of ongoing debates. Our group has recently designed and evaluated a first target panel of 80 candidate genes for T-LBL. The present study aimed at developing a novel optimized gene panel for large-scale application and to promote an international agreement on a common core panel. Small sequence variants obtained from our former study were systematically analyzed and classified with regards to pathogenic relevance, to prioritize candidate genes. Additional genes were curated from literature and online databases for a more comprehensive analysis of relevant functions and signaling pathways. The new target panel TGP-T-LBL entails 84 candidate genes which are key actors in NOTCH, PI3K-AKT, JAK-STAT, RAS signaling, epigenetic regulation, transcription, DNA repair, cell cycle regulation, and ribosomal function. From our former gene panel, 35 out of 80 candidate genes were selected for the novel panel. Forty-six out of 84 genes are currently being analyzed in the ongoing international trial LBL2018. Exploratory analysis of prognostic relevance on mutation-level suggested a potential association of PIK3CA variants c.1624G>A(p.Glu542Lys) and c.1633G>A(p.Glu545Lys) to occurrence of relapse, emphasizing particular relevance of mutation analysis in PI3K-AKT signaling. Our approach promotes comprehensive and clinically relevant mutational profiling of pediatric T-LBL.Low incidence and molecular heterogeneity of pediatric T-cell lymphoblastic lymphoma (T-LBL) require an international, large-scale effort to identify novel clinical biomarkers. The ongoing international clinical trial LBL2018 (NCT04043494) represents an ideal opportunity to implement a common analytic approach. Targeted next-generation sequencing is well-suited for this purpose; however, selection of relevant target genes for T-LBL remains subject of ongoing debates. Our group has recently designed and evaluated a first target panel of 80 candidate genes for T-LBL. The present study aimed at developing a novel optimized gene panel for large-scale application and to promote an international agreement on a common core panel. Small sequence variants obtained from our former study were systematically analyzed and classified with regards to pathogenic relevance, to prioritize candidate genes. Additional genes were curated from literature and online databases for a more comprehensive analysis of relevant functions and signaling pathways. The new target panel TGP-T-LBL entails 84 candidate genes which are key actors in NOTCH, PI3K-AKT, JAK-STAT, RAS signaling, epigenetic regulation, transcription, DNA repair, cell cycle regulation, and ribosomal function. From our former gene panel, 35 out of 80 candidate genes were selected for the novel panel. Forty-six out of 84 genes are currently being analyzed in the ongoing international trial LBL2018. Exploratory analysis of prognostic relevance on mutation-level suggested a potential association of PIK3CA variants c.1624G>A(p.Glu542Lys) and c.1633G>A(p.Glu545Lys) to occurrence of relapse, emphasizing particular relevance of mutation analysis in PI3K-AKT signaling. Our approach promotes comprehensive and clinically relevant mutational profiling of pediatric T-LBL.
Author Khanam, Tasneem
Ruether, Charlotte
Burkhardt, Birgit
Michgehl, Ulf
Wuensch, Christian
Dugas, Martin
Trautmann, Marcel
Sandmann, Sarah
Randau, Gerrit
Hartmann, Wolfgang
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Issue 8
Keywords variant classification
clinical trials
targeted gene panel
pediatric oncology
lymphoblastic lymphoma
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2022 The Authors. Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.
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Notes Funding information
Tasneem Khanam and Birgit Burkhardt contributed equally.
Deutsche Kinderkrebsstiftung, Grant/Award Numbers: 2016.24, 2018.21; Deutsche Krebshilfe, Grant/Award Number: 111347; José Carreras Leukämie‐Stiftung, Grant/Award Number: 05 PSG/2017
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Snippet Low incidence and molecular heterogeneity of pediatric T‐cell lymphoblastic lymphoma (T‐LBL) require an international, large‐scale effort to identify novel...
Low incidence and molecular heterogeneity of pediatric T-cell lymphoblastic lymphoma (T-LBL) require an international, large-scale effort to identify novel...
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StartPage 459
SubjectTerms 1-Phosphatidylinositol 3-kinase
AKT protein
Biology
Cell cycle
Child
clinical trials
Deoxyribonucleic acid
DNA
DNA repair
DNA sequencing
Epigenesis, Genetic
Epigenetics
Gene regulation
Genes
High-Throughput Nucleotide Sequencing
Humans
lymphoblastic lymphoma
Lymphoma
Lymphoma, T-Cell - genetics
Mutation
Neoplasm Recurrence, Local - genetics
pediatric oncology
Pediatrics
Phosphatidylinositol 3-Kinases - genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics
Proto-Oncogene Proteins c-akt - genetics
Sequence Analysis, DNA
T-Lymphocytes
targeted gene panel
variant classification
Title Design of a targeted next‐generation DNA sequencing panel for pediatric T‐cell lymphoblastic lymphoma to unravel biology and optimize treatment
URI https://onlinelibrary.wiley.com/doi/abs/10.1002%2Fgcc.23037
https://www.ncbi.nlm.nih.gov/pubmed/35278000
https://www.proquest.com/docview/2675449012
https://www.proquest.com/docview/2638748023
Volume 61
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