CLINICAL AND BIOLOGICAL LANDSCAPE OF DRIVER MUTATIONS IN PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA
(Abstract release date: 05/19/16)
EHA Library. Ueno H. 06/10/16; 133144; P156
Mr. Hiroo Ueno
Contributions
Contributions
Abstract
Abstract: P156
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
B-progenitor acute lymphoblastic leukemia (B-ALLs) accounts for 85% of pediatric ALL and currently categorized into molecular subgroups according to their ploidy and recurrent translocations, such as ETV6 -RUNX1 (TEL-AML1), TCF3-PBX1 (E2A-PBX1), BCR-ABL1 or MLL-rearrangements. In addition, recent genetic studies using high-throughput sequencing have disclosed a number of novel gene mutations in each subgroup. However, the landscape of driver mutations and their relevance to clinical outcome have not been fully investigated in a large cohort of B-ALL patients.
Aims
The purpose of this study is to characterize the distribution of genetic alterations and their clinical relevance in pediatric B-ALLs using high-throughput sequencing in a large cohort of B-ALL patients.
Methods
A total of 524 pediatric B-ALL patients were enrolled in this study, who were uniformly treated according to the Japan Association of Childhood Leukemia Study (JACLS) ALL-02 protocol between 2002 and 2008. These patients were categorized into three risk groups, including standard risk, high risk, and extremely high risk. Infantile, BCR-ABL1–positive and Down syndrome–associated ALLs were not enrolled in this cohort. A total of 158 known or putative driver genes in pediatric ALL were analyzed for somatic mutations by targeted-capture deep sequencing using SureSelect (Agilent). Single nucleotide polymorphism-baits were also included, which were designed to allow for genome-wide copy number detection based on deep sequencing.
Results
The median age at diagnosis and observation period were 5.2 years (1-18.5) and 4.2 years (1.8-9), respectively. Sixty-six of the 524 patients (13%) had relapsed diseases and 47 patients (9%) were dead. Real-time RT-PCR and conventional cytogenetic analyses revealed ETV6-RUNX1, TCF3-PBX1, MLL rearrangements, hyperdiploidy (> 50 chromosomes) and hypodiploidy (<44 chromosomes) in 113 (22%), 42 (8%), 10 (2%), 95 (18%), and 2 (0.4%) patients, respectively, and the remaining 262 patients (50%) had none of these abnormalities. The mean depth of the targeted sequencing was 569× across the entire cohort. In total, 74% of the patients harbored at least one mutation (median, 2 per patient; range, 0-9), and the mean number of mutations in ETV6-RUNX1, TCF3-PBX1, MLL-rearranged, hyperdiploid, hypodiploid ALLs were 0.63, 1.19, 1, 3.05 and 4, respectively. CDKN2A, KRAS, NRAS, PAX5, and ETV6 were among the most frequently affected genes, which were mutated or deleted in 24%, 21%, 18%, 18%, and 15% of the cases, respectively. In terms of functional pathways, RAS pathway was most frequently affected and altered as many as 50% of the patients, followed by the pathways involved in epigenetic regulation, cell cycle, and B-cell development. Frequency of mutations showed a significant variation among B-ALL subtypes. For instance, RAS pathway mutations were detected in as many as 87 % of hyperdiploid ALLs, compared to 3 % of TCF3-PBX1 ALLs. On the other hand, IKZF1 mutations/deletions were only indentified in those without recurrent translocations, hyperdiploidy and hypodiploidy.
Conclusion
We revealed the landscape of driver mutations and copy number alterations in pediatric B-ALL and their diversity in B-ALL subtypes. Further analyses are underway to better clarify the prognostic significance of driver gene mutations.
Session topic: Acute lymphoblastic leukemia - Biology 1
Keyword(s): Acute lymphoblastic leukemia, Genetic, Pediatric
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
B-progenitor acute lymphoblastic leukemia (B-ALLs) accounts for 85% of pediatric ALL and currently categorized into molecular subgroups according to their ploidy and recurrent translocations, such as ETV6 -RUNX1 (TEL-AML1), TCF3-PBX1 (E2A-PBX1), BCR-ABL1 or MLL-rearrangements. In addition, recent genetic studies using high-throughput sequencing have disclosed a number of novel gene mutations in each subgroup. However, the landscape of driver mutations and their relevance to clinical outcome have not been fully investigated in a large cohort of B-ALL patients.
Aims
The purpose of this study is to characterize the distribution of genetic alterations and their clinical relevance in pediatric B-ALLs using high-throughput sequencing in a large cohort of B-ALL patients.
Methods
A total of 524 pediatric B-ALL patients were enrolled in this study, who were uniformly treated according to the Japan Association of Childhood Leukemia Study (JACLS) ALL-02 protocol between 2002 and 2008. These patients were categorized into three risk groups, including standard risk, high risk, and extremely high risk. Infantile, BCR-ABL1–positive and Down syndrome–associated ALLs were not enrolled in this cohort. A total of 158 known or putative driver genes in pediatric ALL were analyzed for somatic mutations by targeted-capture deep sequencing using SureSelect (Agilent). Single nucleotide polymorphism-baits were also included, which were designed to allow for genome-wide copy number detection based on deep sequencing.
Results
The median age at diagnosis and observation period were 5.2 years (1-18.5) and 4.2 years (1.8-9), respectively. Sixty-six of the 524 patients (13%) had relapsed diseases and 47 patients (9%) were dead. Real-time RT-PCR and conventional cytogenetic analyses revealed ETV6-RUNX1, TCF3-PBX1, MLL rearrangements, hyperdiploidy (> 50 chromosomes) and hypodiploidy (<44 chromosomes) in 113 (22%), 42 (8%), 10 (2%), 95 (18%), and 2 (0.4%) patients, respectively, and the remaining 262 patients (50%) had none of these abnormalities. The mean depth of the targeted sequencing was 569× across the entire cohort. In total, 74% of the patients harbored at least one mutation (median, 2 per patient; range, 0-9), and the mean number of mutations in ETV6-RUNX1, TCF3-PBX1, MLL-rearranged, hyperdiploid, hypodiploid ALLs were 0.63, 1.19, 1, 3.05 and 4, respectively. CDKN2A, KRAS, NRAS, PAX5, and ETV6 were among the most frequently affected genes, which were mutated or deleted in 24%, 21%, 18%, 18%, and 15% of the cases, respectively. In terms of functional pathways, RAS pathway was most frequently affected and altered as many as 50% of the patients, followed by the pathways involved in epigenetic regulation, cell cycle, and B-cell development. Frequency of mutations showed a significant variation among B-ALL subtypes. For instance, RAS pathway mutations were detected in as many as 87 % of hyperdiploid ALLs, compared to 3 % of TCF3-PBX1 ALLs. On the other hand, IKZF1 mutations/deletions were only indentified in those without recurrent translocations, hyperdiploidy and hypodiploidy.
Conclusion
We revealed the landscape of driver mutations and copy number alterations in pediatric B-ALL and their diversity in B-ALL subtypes. Further analyses are underway to better clarify the prognostic significance of driver gene mutations.
Session topic: Acute lymphoblastic leukemia - Biology 1
Keyword(s): Acute lymphoblastic leukemia, Genetic, Pediatric
Abstract: P156
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
B-progenitor acute lymphoblastic leukemia (B-ALLs) accounts for 85% of pediatric ALL and currently categorized into molecular subgroups according to their ploidy and recurrent translocations, such as ETV6 -RUNX1 (TEL-AML1), TCF3-PBX1 (E2A-PBX1), BCR-ABL1 or MLL-rearrangements. In addition, recent genetic studies using high-throughput sequencing have disclosed a number of novel gene mutations in each subgroup. However, the landscape of driver mutations and their relevance to clinical outcome have not been fully investigated in a large cohort of B-ALL patients.
Aims
The purpose of this study is to characterize the distribution of genetic alterations and their clinical relevance in pediatric B-ALLs using high-throughput sequencing in a large cohort of B-ALL patients.
Methods
A total of 524 pediatric B-ALL patients were enrolled in this study, who were uniformly treated according to the Japan Association of Childhood Leukemia Study (JACLS) ALL-02 protocol between 2002 and 2008. These patients were categorized into three risk groups, including standard risk, high risk, and extremely high risk. Infantile, BCR-ABL1–positive and Down syndrome–associated ALLs were not enrolled in this cohort. A total of 158 known or putative driver genes in pediatric ALL were analyzed for somatic mutations by targeted-capture deep sequencing using SureSelect (Agilent). Single nucleotide polymorphism-baits were also included, which were designed to allow for genome-wide copy number detection based on deep sequencing.
Results
The median age at diagnosis and observation period were 5.2 years (1-18.5) and 4.2 years (1.8-9), respectively. Sixty-six of the 524 patients (13%) had relapsed diseases and 47 patients (9%) were dead. Real-time RT-PCR and conventional cytogenetic analyses revealed ETV6-RUNX1, TCF3-PBX1, MLL rearrangements, hyperdiploidy (> 50 chromosomes) and hypodiploidy (<44 chromosomes) in 113 (22%), 42 (8%), 10 (2%), 95 (18%), and 2 (0.4%) patients, respectively, and the remaining 262 patients (50%) had none of these abnormalities. The mean depth of the targeted sequencing was 569× across the entire cohort. In total, 74% of the patients harbored at least one mutation (median, 2 per patient; range, 0-9), and the mean number of mutations in ETV6-RUNX1, TCF3-PBX1, MLL-rearranged, hyperdiploid, hypodiploid ALLs were 0.63, 1.19, 1, 3.05 and 4, respectively. CDKN2A, KRAS, NRAS, PAX5, and ETV6 were among the most frequently affected genes, which were mutated or deleted in 24%, 21%, 18%, 18%, and 15% of the cases, respectively. In terms of functional pathways, RAS pathway was most frequently affected and altered as many as 50% of the patients, followed by the pathways involved in epigenetic regulation, cell cycle, and B-cell development. Frequency of mutations showed a significant variation among B-ALL subtypes. For instance, RAS pathway mutations were detected in as many as 87 % of hyperdiploid ALLs, compared to 3 % of TCF3-PBX1 ALLs. On the other hand, IKZF1 mutations/deletions were only indentified in those without recurrent translocations, hyperdiploidy and hypodiploidy.
Conclusion
We revealed the landscape of driver mutations and copy number alterations in pediatric B-ALL and their diversity in B-ALL subtypes. Further analyses are underway to better clarify the prognostic significance of driver gene mutations.
Session topic: Acute lymphoblastic leukemia - Biology 1
Keyword(s): Acute lymphoblastic leukemia, Genetic, Pediatric
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
B-progenitor acute lymphoblastic leukemia (B-ALLs) accounts for 85% of pediatric ALL and currently categorized into molecular subgroups according to their ploidy and recurrent translocations, such as ETV6 -RUNX1 (TEL-AML1), TCF3-PBX1 (E2A-PBX1), BCR-ABL1 or MLL-rearrangements. In addition, recent genetic studies using high-throughput sequencing have disclosed a number of novel gene mutations in each subgroup. However, the landscape of driver mutations and their relevance to clinical outcome have not been fully investigated in a large cohort of B-ALL patients.
Aims
The purpose of this study is to characterize the distribution of genetic alterations and their clinical relevance in pediatric B-ALLs using high-throughput sequencing in a large cohort of B-ALL patients.
Methods
A total of 524 pediatric B-ALL patients were enrolled in this study, who were uniformly treated according to the Japan Association of Childhood Leukemia Study (JACLS) ALL-02 protocol between 2002 and 2008. These patients were categorized into three risk groups, including standard risk, high risk, and extremely high risk. Infantile, BCR-ABL1–positive and Down syndrome–associated ALLs were not enrolled in this cohort. A total of 158 known or putative driver genes in pediatric ALL were analyzed for somatic mutations by targeted-capture deep sequencing using SureSelect (Agilent). Single nucleotide polymorphism-baits were also included, which were designed to allow for genome-wide copy number detection based on deep sequencing.
Results
The median age at diagnosis and observation period were 5.2 years (1-18.5) and 4.2 years (1.8-9), respectively. Sixty-six of the 524 patients (13%) had relapsed diseases and 47 patients (9%) were dead. Real-time RT-PCR and conventional cytogenetic analyses revealed ETV6-RUNX1, TCF3-PBX1, MLL rearrangements, hyperdiploidy (> 50 chromosomes) and hypodiploidy (<44 chromosomes) in 113 (22%), 42 (8%), 10 (2%), 95 (18%), and 2 (0.4%) patients, respectively, and the remaining 262 patients (50%) had none of these abnormalities. The mean depth of the targeted sequencing was 569× across the entire cohort. In total, 74% of the patients harbored at least one mutation (median, 2 per patient; range, 0-9), and the mean number of mutations in ETV6-RUNX1, TCF3-PBX1, MLL-rearranged, hyperdiploid, hypodiploid ALLs were 0.63, 1.19, 1, 3.05 and 4, respectively. CDKN2A, KRAS, NRAS, PAX5, and ETV6 were among the most frequently affected genes, which were mutated or deleted in 24%, 21%, 18%, 18%, and 15% of the cases, respectively. In terms of functional pathways, RAS pathway was most frequently affected and altered as many as 50% of the patients, followed by the pathways involved in epigenetic regulation, cell cycle, and B-cell development. Frequency of mutations showed a significant variation among B-ALL subtypes. For instance, RAS pathway mutations were detected in as many as 87 % of hyperdiploid ALLs, compared to 3 % of TCF3-PBX1 ALLs. On the other hand, IKZF1 mutations/deletions were only indentified in those without recurrent translocations, hyperdiploidy and hypodiploidy.
Conclusion
We revealed the landscape of driver mutations and copy number alterations in pediatric B-ALL and their diversity in B-ALL subtypes. Further analyses are underway to better clarify the prognostic significance of driver gene mutations.
Session topic: Acute lymphoblastic leukemia - Biology 1
Keyword(s): Acute lymphoblastic leukemia, Genetic, Pediatric
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