CONCURRENT CREBBP AND KRAS MUTATIONS ARE ASSOCIATED WITH A DISMAL OUTCOME IN CHILDREN WITH HYPERDIPLOID LEUKEMIA IMPLYING A SYNERGISTIC FUNCTION IN RELAPSE EVOLUTION
(Abstract release date: 05/21/15)
EHA Library. Panzer-Grumayer R. 06/14/15; 103102; S822
Disclosure(s): Children's Cancer Research Institute
Prof. Dr. Renate Panzer-Grumayer
Contributions
Contributions
Abstract
Abstract: S822
Type: Oral Presentation
Presentation during EHA20: From 14.06.2015 08:30 to 14.06.2015 08:45
Location: Room Stolz 1
Background
High hyperdiploidy (HD) denotes the largest B cell precursor acute lymphoblastic leukemia (BCP ALL) subgroup in children and adolescents. Patients usually present with low risk features and respond well to treatment. The relative proportion of relapses (up to 15%) is small but constitutes the largest genetically homogeneous fraction in the BCP ALL cohort. ≈50% of HD ALL harbor activating mutations in RTK/Ras pathway genes, which, however, do not qualify as relapse predicting factor based on their high instability at relapse. By contrast, mutations in the transcriptional coactivator CREBBP (CBP) occur particularly in ALL relapsing cases, attenuate the function of the encoded protein and reduce acetylation of histone and non-histone proteins. Previous studies have focused on conventional sequencing of selected RTK/Ras pathway genes including small numbers of matched diagnosis and relapse samples only.
Aims
Our aim was, therefore, to investigate the mutational landscape of HD ALL using high throughput sequencing in a large cohort of such relapsing cases, in order to infer and compare the clonal composition of diagnostic and relapse samples, and test for clinical association.
Methods
We used whole exome sequencing (WES; n=19) and targeted sequencing in these and additional 81 relapsing cases (including 50 cases with matched diagnosis and relapse samples) as well as 51 non-relapsing ones. Cases were treated according to AIEOP/BFM-ALL95 and 2000, CoALL-08-09, and ALL-Rez BFM 2002 protocols.
Results
We detected at diagnosis 12 (median, range 3-23) and at relapse 25 (range 10-90) non-silent mutations per case. They target most frequently KRAS, NRAS, PTPN11 and FLT3 as well as CREBBP. Ras mutations were found in >80% of cases, frequently affecting only small clones with high inter- and intragenic heterogeneity at initial diagnosis; ≈50% were lost at relapse. RTK/Ras mutations were similarly frequent at relapse, when the vast majority of them define the major clone. CREBBP mutations were present in 18% of cases at diagnosis and 30% at relapse. They were already part of the major clone in >50% of cases at diagnosis, but were virtually always confined to the predominant relapse clone. Our most salient finding was the coexistence of CREBBP and KRAS mutations in the major clone of HD ALL relapses (P<0.001). Despite a similar frequency of KRAS and NRAS mutations, only the KRAS ones concurred with CREBBP mutations. This observation implies that these two mutations exert an interdependent function and cooperate in a RAS isoform-specific and synergistic fashion under the selective pressure of the applied chemotherapy. Clinically, RTK/Ras pathway and CREBBP mutated relapses showed only a slight prevalence of occurring early while KRAS mutated relapses usually did develop early; in line, relapses with concurrent CREBBP and KRAS mutations appeared earlier than those in the remaining cases (P=0.012). While cases with CREBBP or KRAS mutations or double mutant leukemias had a significantly poorer outcome than wt cases, the cumulative incidence of relapses of the double mutant cases tended to be associated with an increased incidence of subsequent relapses.
Summary
Keyword(s): ALL, Hyperdiploid, Mutation analysis, Relapsed acute lymphoblastic leukemia
Session topic: Towards targeted therapy in ALL
Type: Oral Presentation
Presentation during EHA20: From 14.06.2015 08:30 to 14.06.2015 08:45
Location: Room Stolz 1
Background
High hyperdiploidy (HD) denotes the largest B cell precursor acute lymphoblastic leukemia (BCP ALL) subgroup in children and adolescents. Patients usually present with low risk features and respond well to treatment. The relative proportion of relapses (up to 15%) is small but constitutes the largest genetically homogeneous fraction in the BCP ALL cohort. ≈50% of HD ALL harbor activating mutations in RTK/Ras pathway genes, which, however, do not qualify as relapse predicting factor based on their high instability at relapse. By contrast, mutations in the transcriptional coactivator CREBBP (CBP) occur particularly in ALL relapsing cases, attenuate the function of the encoded protein and reduce acetylation of histone and non-histone proteins. Previous studies have focused on conventional sequencing of selected RTK/Ras pathway genes including small numbers of matched diagnosis and relapse samples only.
Aims
Our aim was, therefore, to investigate the mutational landscape of HD ALL using high throughput sequencing in a large cohort of such relapsing cases, in order to infer and compare the clonal composition of diagnostic and relapse samples, and test for clinical association.
Methods
We used whole exome sequencing (WES; n=19) and targeted sequencing in these and additional 81 relapsing cases (including 50 cases with matched diagnosis and relapse samples) as well as 51 non-relapsing ones. Cases were treated according to AIEOP/BFM-ALL95 and 2000, CoALL-08-09, and ALL-Rez BFM 2002 protocols.
Results
We detected at diagnosis 12 (median, range 3-23) and at relapse 25 (range 10-90) non-silent mutations per case. They target most frequently KRAS, NRAS, PTPN11 and FLT3 as well as CREBBP. Ras mutations were found in >80% of cases, frequently affecting only small clones with high inter- and intragenic heterogeneity at initial diagnosis; ≈50% were lost at relapse. RTK/Ras mutations were similarly frequent at relapse, when the vast majority of them define the major clone. CREBBP mutations were present in 18% of cases at diagnosis and 30% at relapse. They were already part of the major clone in >50% of cases at diagnosis, but were virtually always confined to the predominant relapse clone. Our most salient finding was the coexistence of CREBBP and KRAS mutations in the major clone of HD ALL relapses (P<0.001). Despite a similar frequency of KRAS and NRAS mutations, only the KRAS ones concurred with CREBBP mutations. This observation implies that these two mutations exert an interdependent function and cooperate in a RAS isoform-specific and synergistic fashion under the selective pressure of the applied chemotherapy. Clinically, RTK/Ras pathway and CREBBP mutated relapses showed only a slight prevalence of occurring early while KRAS mutated relapses usually did develop early; in line, relapses with concurrent CREBBP and KRAS mutations appeared earlier than those in the remaining cases (P=0.012). While cases with CREBBP or KRAS mutations or double mutant leukemias had a significantly poorer outcome than wt cases, the cumulative incidence of relapses of the double mutant cases tended to be associated with an increased incidence of subsequent relapses.
Summary
KRAS and CREBBP double mutant HD ALL relapse cases are amongst those with the highest risk and are therefore suitable candidates for novel therapeutic approaches using histone deacetylase inhibitors and Ras pathway inhibitors. Since somatic CREBBP mutations are also present in a small number of non-relapsing HD ALL cases, they cannot be used as prognostic markers.
Keyword(s): ALL, Hyperdiploid, Mutation analysis, Relapsed acute lymphoblastic leukemia
Session topic: Towards targeted therapy in ALL
Abstract: S822
Type: Oral Presentation
Presentation during EHA20: From 14.06.2015 08:30 to 14.06.2015 08:45
Location: Room Stolz 1
Background
High hyperdiploidy (HD) denotes the largest B cell precursor acute lymphoblastic leukemia (BCP ALL) subgroup in children and adolescents. Patients usually present with low risk features and respond well to treatment. The relative proportion of relapses (up to 15%) is small but constitutes the largest genetically homogeneous fraction in the BCP ALL cohort. ≈50% of HD ALL harbor activating mutations in RTK/Ras pathway genes, which, however, do not qualify as relapse predicting factor based on their high instability at relapse. By contrast, mutations in the transcriptional coactivator CREBBP (CBP) occur particularly in ALL relapsing cases, attenuate the function of the encoded protein and reduce acetylation of histone and non-histone proteins. Previous studies have focused on conventional sequencing of selected RTK/Ras pathway genes including small numbers of matched diagnosis and relapse samples only.
Aims
Our aim was, therefore, to investigate the mutational landscape of HD ALL using high throughput sequencing in a large cohort of such relapsing cases, in order to infer and compare the clonal composition of diagnostic and relapse samples, and test for clinical association.
Methods
We used whole exome sequencing (WES; n=19) and targeted sequencing in these and additional 81 relapsing cases (including 50 cases with matched diagnosis and relapse samples) as well as 51 non-relapsing ones. Cases were treated according to AIEOP/BFM-ALL95 and 2000, CoALL-08-09, and ALL-Rez BFM 2002 protocols.
Results
We detected at diagnosis 12 (median, range 3-23) and at relapse 25 (range 10-90) non-silent mutations per case. They target most frequently KRAS, NRAS, PTPN11 and FLT3 as well as CREBBP. Ras mutations were found in >80% of cases, frequently affecting only small clones with high inter- and intragenic heterogeneity at initial diagnosis; ≈50% were lost at relapse. RTK/Ras mutations were similarly frequent at relapse, when the vast majority of them define the major clone. CREBBP mutations were present in 18% of cases at diagnosis and 30% at relapse. They were already part of the major clone in >50% of cases at diagnosis, but were virtually always confined to the predominant relapse clone. Our most salient finding was the coexistence of CREBBP and KRAS mutations in the major clone of HD ALL relapses (P<0.001). Despite a similar frequency of KRAS and NRAS mutations, only the KRAS ones concurred with CREBBP mutations. This observation implies that these two mutations exert an interdependent function and cooperate in a RAS isoform-specific and synergistic fashion under the selective pressure of the applied chemotherapy. Clinically, RTK/Ras pathway and CREBBP mutated relapses showed only a slight prevalence of occurring early while KRAS mutated relapses usually did develop early; in line, relapses with concurrent CREBBP and KRAS mutations appeared earlier than those in the remaining cases (P=0.012). While cases with CREBBP or KRAS mutations or double mutant leukemias had a significantly poorer outcome than wt cases, the cumulative incidence of relapses of the double mutant cases tended to be associated with an increased incidence of subsequent relapses.
Summary
Keyword(s): ALL, Hyperdiploid, Mutation analysis, Relapsed acute lymphoblastic leukemia
Session topic: Towards targeted therapy in ALL
Type: Oral Presentation
Presentation during EHA20: From 14.06.2015 08:30 to 14.06.2015 08:45
Location: Room Stolz 1
Background
High hyperdiploidy (HD) denotes the largest B cell precursor acute lymphoblastic leukemia (BCP ALL) subgroup in children and adolescents. Patients usually present with low risk features and respond well to treatment. The relative proportion of relapses (up to 15%) is small but constitutes the largest genetically homogeneous fraction in the BCP ALL cohort. ≈50% of HD ALL harbor activating mutations in RTK/Ras pathway genes, which, however, do not qualify as relapse predicting factor based on their high instability at relapse. By contrast, mutations in the transcriptional coactivator CREBBP (CBP) occur particularly in ALL relapsing cases, attenuate the function of the encoded protein and reduce acetylation of histone and non-histone proteins. Previous studies have focused on conventional sequencing of selected RTK/Ras pathway genes including small numbers of matched diagnosis and relapse samples only.
Aims
Our aim was, therefore, to investigate the mutational landscape of HD ALL using high throughput sequencing in a large cohort of such relapsing cases, in order to infer and compare the clonal composition of diagnostic and relapse samples, and test for clinical association.
Methods
We used whole exome sequencing (WES; n=19) and targeted sequencing in these and additional 81 relapsing cases (including 50 cases with matched diagnosis and relapse samples) as well as 51 non-relapsing ones. Cases were treated according to AIEOP/BFM-ALL95 and 2000, CoALL-08-09, and ALL-Rez BFM 2002 protocols.
Results
We detected at diagnosis 12 (median, range 3-23) and at relapse 25 (range 10-90) non-silent mutations per case. They target most frequently KRAS, NRAS, PTPN11 and FLT3 as well as CREBBP. Ras mutations were found in >80% of cases, frequently affecting only small clones with high inter- and intragenic heterogeneity at initial diagnosis; ≈50% were lost at relapse. RTK/Ras mutations were similarly frequent at relapse, when the vast majority of them define the major clone. CREBBP mutations were present in 18% of cases at diagnosis and 30% at relapse. They were already part of the major clone in >50% of cases at diagnosis, but were virtually always confined to the predominant relapse clone. Our most salient finding was the coexistence of CREBBP and KRAS mutations in the major clone of HD ALL relapses (P<0.001). Despite a similar frequency of KRAS and NRAS mutations, only the KRAS ones concurred with CREBBP mutations. This observation implies that these two mutations exert an interdependent function and cooperate in a RAS isoform-specific and synergistic fashion under the selective pressure of the applied chemotherapy. Clinically, RTK/Ras pathway and CREBBP mutated relapses showed only a slight prevalence of occurring early while KRAS mutated relapses usually did develop early; in line, relapses with concurrent CREBBP and KRAS mutations appeared earlier than those in the remaining cases (P=0.012). While cases with CREBBP or KRAS mutations or double mutant leukemias had a significantly poorer outcome than wt cases, the cumulative incidence of relapses of the double mutant cases tended to be associated with an increased incidence of subsequent relapses.
Summary
KRAS and CREBBP double mutant HD ALL relapse cases are amongst those with the highest risk and are therefore suitable candidates for novel therapeutic approaches using histone deacetylase inhibitors and Ras pathway inhibitors. Since somatic CREBBP mutations are also present in a small number of non-relapsing HD ALL cases, they cannot be used as prognostic markers.
Keyword(s): ALL, Hyperdiploid, Mutation analysis, Relapsed acute lymphoblastic leukemia
Session topic: Towards targeted therapy in ALL
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