Next generation sequencing as a tool for pharmacogenomic profiling: Nine novel potential genetic markers for targeted therapy in childhood acute lymphoblastic leukemia
Introduction/Objective. Next generation sequencing (NGS) technology has enabled genomic profiling of each patient. Growing knowledge in pharmacogenomics makes it possible to use NGS data for discovery of novel potential genetic markers for targeted therapy of many diseases, especially cancers. The a...
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doaj-7346efb0264744f386f6dc1cda0fde082021-01-02T05:27:51ZengSerbian Medical SocietySrpski Arhiv za Celokupno Lekarstvo0370-81792406-08952018-01-011467-840741110.2298/SARH171003194D0370-81791700194DNext generation sequencing as a tool for pharmacogenomic profiling: Nine novel potential genetic markers for targeted therapy in childhood acute lymphoblastic leukemiaDokmanović Lidija0Milošević Goran1Perić Jelena2Tošić Nataša3Krstovski Nada4Janić Dragana5Pavlović Sonja6University Children’s Hospital, Belgrade + School of Medicine, BelgradeUniversity Children’s Hospital, BelgradeInstitute for Molecular Genetics and Genetic Engineering, BelgradeInstitute for Molecular Genetics and Genetic Engineering, BelgradeUniversity Children’s Hospital, Belgrade + School of Medicine, BelgradeUniversity Children’s Hospital, Belgrade + School of Medicine, BelgradeInstitute for Molecular Genetics and Genetic Engineering, BelgradeIntroduction/Objective. Next generation sequencing (NGS) technology has enabled genomic profiling of each patient. Growing knowledge in pharmacogenomics makes it possible to use NGS data for discovery of novel potential genetic markers for targeted therapy of many diseases, especially cancers. The aim of this study was to use targeted NGS to make a genetic profile of childhood acute lymphoblastic leukemia (cALL) in order to evaluate potential molecular targets for targeted therapy. Methods. We analyzed DNA samples from 17 cALL patients using NGS targeted sequencing. Advanced bioinformatic analysis was used to identify novel mutations in analyzed genes and to predict their effect and pharmacogenomic potential. Results. We identified nine variants that have not been previously reported in relevant databases, including two stop-gain variants, ABL1 p.Q252* and AKT1 p.W22*, one frameshift, STK11 p.G257fs*28, and six missense variants. We created three-dimensional models of four proteins harboring novel missense variants. We analyzed pharmacogenomic potential of each variant and found that two of them, STK11 c.1023G>T/ p.L341F and ERBB2 c.2341C>T/ p.R781W, are suitable candidates for targeted therapy. Conclusion. Most new variants detected in this study were found in the genes associated with Ras signaling pathway, which is frequently mutated in cALL patients. Pharmacogenomic profiling of each cALL will be indispensable for novel therapy approaches. Detection and initial analysis of novel variants, presented in this study, will become a standard procedure for the design and development of individualized therapies for children with ALL, leading to improved patient outcomes. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. III41004]http://www.doiserbia.nb.rs/img/doi/0370-8179/2018/0370-81791700194D.pdfpharmacogenomicsnext generation sequencingacute lymphoblastic leukemiamolecular targeted therapy |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Dokmanović Lidija Milošević Goran Perić Jelena Tošić Nataša Krstovski Nada Janić Dragana Pavlović Sonja |
spellingShingle |
Dokmanović Lidija Milošević Goran Perić Jelena Tošić Nataša Krstovski Nada Janić Dragana Pavlović Sonja Next generation sequencing as a tool for pharmacogenomic profiling: Nine novel potential genetic markers for targeted therapy in childhood acute lymphoblastic leukemia Srpski Arhiv za Celokupno Lekarstvo pharmacogenomics next generation sequencing acute lymphoblastic leukemia molecular targeted therapy |
author_facet |
Dokmanović Lidija Milošević Goran Perić Jelena Tošić Nataša Krstovski Nada Janić Dragana Pavlović Sonja |
author_sort |
Dokmanović Lidija |
title |
Next generation sequencing as a tool for pharmacogenomic profiling: Nine novel potential genetic markers for targeted therapy in childhood acute lymphoblastic leukemia |
title_short |
Next generation sequencing as a tool for pharmacogenomic profiling: Nine novel potential genetic markers for targeted therapy in childhood acute lymphoblastic leukemia |
title_full |
Next generation sequencing as a tool for pharmacogenomic profiling: Nine novel potential genetic markers for targeted therapy in childhood acute lymphoblastic leukemia |
title_fullStr |
Next generation sequencing as a tool for pharmacogenomic profiling: Nine novel potential genetic markers for targeted therapy in childhood acute lymphoblastic leukemia |
title_full_unstemmed |
Next generation sequencing as a tool for pharmacogenomic profiling: Nine novel potential genetic markers for targeted therapy in childhood acute lymphoblastic leukemia |
title_sort |
next generation sequencing as a tool for pharmacogenomic profiling: nine novel potential genetic markers for targeted therapy in childhood acute lymphoblastic leukemia |
publisher |
Serbian Medical Society |
series |
Srpski Arhiv za Celokupno Lekarstvo |
issn |
0370-8179 2406-0895 |
publishDate |
2018-01-01 |
description |
Introduction/Objective. Next generation sequencing (NGS) technology has enabled genomic profiling of each patient. Growing knowledge in pharmacogenomics makes it possible to use NGS data for discovery of novel potential genetic markers for targeted therapy of many diseases, especially cancers. The aim of this study was to use targeted NGS to make a genetic profile of childhood acute lymphoblastic leukemia (cALL) in order to evaluate potential molecular targets for targeted therapy. Methods. We analyzed DNA samples from 17 cALL patients using NGS targeted sequencing. Advanced bioinformatic analysis was used to identify novel mutations in analyzed genes and to predict their effect and pharmacogenomic potential. Results. We identified nine variants that have not been previously reported in relevant databases, including two stop-gain variants, ABL1 p.Q252* and AKT1 p.W22*, one frameshift, STK11 p.G257fs*28, and six missense variants. We created three-dimensional models of four proteins harboring novel missense variants. We analyzed pharmacogenomic potential of each variant and found that two of them, STK11 c.1023G>T/ p.L341F and ERBB2 c.2341C>T/ p.R781W, are suitable candidates for targeted therapy. Conclusion. Most new variants detected in this study were found in the genes associated with Ras signaling pathway, which is frequently mutated in cALL patients. Pharmacogenomic profiling of each cALL will be indispensable for novel therapy approaches. Detection and initial analysis of novel variants, presented in this study, will become a standard procedure for the design and development of individualized therapies for children with ALL, leading to improved patient outcomes. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. III41004] |
topic |
pharmacogenomics next generation sequencing acute lymphoblastic leukemia molecular targeted therapy |
url |
http://www.doiserbia.nb.rs/img/doi/0370-8179/2018/0370-81791700194D.pdf |
work_keys_str_mv |
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