MUTATIONAL STATUS OF NRAS, KRAS AND PTPN11 GENES IS ASSOCIATED WITH GENETIC/CYTOGENETIC FEATURES IN CHILDREN WITH B-PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA
(Abstract release date: 05/19/16)
EHA Library. Liang D. 06/10/16; 133151; P163
Prof. Der-Cherng Liang
Contributions
Contributions
Abstract
Abstract: P163
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
The activating mutations in RAS signaling pathway including NRAS, KRAS and PTPN11 genes have been described in B-precursor acute lymphoblastic leukemia (ALL). However, the correlation of RAS pathway gene mutations with recurrent genetic abnormalities was not addressed.
Aims
We aimed to investigate the frequencies, and the association with genetic/cytogenetic abnormalities as well as prognostic relevance of RAS pathway mutations in Taiwanese children with B-precursor ALL, the largest cohort in Asians.
Methods
Between 1995 and 2012, bone marrow samples at diagnosis from 538 children were studied. Mutations at codons 12, 13, and 61 in exons 1 and 2 of NRAS and KRAS genes, as well as the entire coding region of PTPN11 were analyzed using PCR-based assay followed by direct sequencing. The mutational status of each gene was correlated with the clinico-hematological features, recurrent genetic abnormalities, and outcomes for those treated with TPOG-ALL-2002 protocol (n = 348).
Results
The frequencies of NRAS, KRAS, and PTPN11 mutations were 10.5% (56/533), 10.1% (54/533), and 3.4% (18/529), respectively. Mutations of NRAS, KRAS, and PTPN11 were mutually exclusive with rare exception, including 4 co-occurrence of NRAS and KRAS mutations, and 2 co-existence of KRAS and PTPN11 mutations. Together, 23.0% of B-precursor ALL patients had gene mutations involving RAS signaling pathway. No differences in age, Hb level, WBC or platelet counts were observed in patients with or without NRAS and PTPN11 mutations. The frequency of PTPN11 mutations was significantly higher in girls than in boys (1.4% vs. 6.0%, P = 0.006). Patients with KRAS mutations presented with significantly younger age (P = 0.004) and lower platelet counts (P = 0.007). Only one out of 21BCR-ABL1 ALL had a mutation (NRAS) in RAS pathway. ETV6/RUNX1 was associated with a lower frequency of NRAS mutations (2.2% vs. 12.3%, P = 0.002) and a trend of less PTPN11 mutations (0% vs. 4.1%, P = 0.053); none of patients with TCF3/PBX1 had KRAS mutation (P = 0.024) whereas 2 of the 3 hypodiploid ALL had KRAS mutations (P = 0.028); KRAS mutations occurred more frequently in patients with MLL rearranged (23.5% vs. 9.2%, P = 0.014, but the difference was not significant if we excluded infant ALL (n = 30) (20% vs. 8.7%, P = 0.223). NRAS mutations were more commonly detected in hyperdiploid ALL (18.0% vs. 9.5%, P = 0.069). Patients without specific genetic/cytogenetic subtypes had a significantly lower frequency of NRAS mutations as compared to those without any of these recurrent genetic abnormalities (7.5% vs. 13.2%, P = 0.048) and a higher rate of PTPN11 mutations (5.0% vs. 1.6%, P = 0.051). There were no differences in 5-year EFS and OS with regard to mutational status of NRAS (70.7% vs. 79.0%, P = 0.575; 89.6% vs. 82.3%, P = 0.863, respectively) and of PTPN11 (80.8% vs. 77.7%, P = 0.490; 90.0% vs. 82.2%, P = 0.317, respectively). KRAS mutations were associated with inferior outcomes (66.0% vs. 79.7%, P = 0.039 for EFS and 74.8% vs. 84.0%, P = 0.058 for OS) but there was no difference in non-infant ALL (P = 0.381 for EFS and P = 0.635 for OS).
Conclusion
Patients with recurrent genetic abnormalities had rare occurrence of RAS pathway mutations in non-infant pediatric B-precursor ALL. NRAS mutations were more frequently detected in patients with hyperdiploidy, whereas KRAS mutations were highly associated with infant ALL with MLL rearranged. (Grants support: MMH-E-99009, MOST103-2314-B-195-008-MY3, MOST104-2314-B-182-032-MY3, OMRPG3C0021 and grant from Terry Fox Foundation)
Session topic: Acute lymphoblastic leukemia - Biology 2
Keyword(s): B cell acute lymphoblastic leukemia, Cytogenetic abnormalities, PTPN11, Ras
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
The activating mutations in RAS signaling pathway including NRAS, KRAS and PTPN11 genes have been described in B-precursor acute lymphoblastic leukemia (ALL). However, the correlation of RAS pathway gene mutations with recurrent genetic abnormalities was not addressed.
Aims
We aimed to investigate the frequencies, and the association with genetic/cytogenetic abnormalities as well as prognostic relevance of RAS pathway mutations in Taiwanese children with B-precursor ALL, the largest cohort in Asians.
Methods
Between 1995 and 2012, bone marrow samples at diagnosis from 538 children were studied. Mutations at codons 12, 13, and 61 in exons 1 and 2 of NRAS and KRAS genes, as well as the entire coding region of PTPN11 were analyzed using PCR-based assay followed by direct sequencing. The mutational status of each gene was correlated with the clinico-hematological features, recurrent genetic abnormalities, and outcomes for those treated with TPOG-ALL-2002 protocol (n = 348).
Results
The frequencies of NRAS, KRAS, and PTPN11 mutations were 10.5% (56/533), 10.1% (54/533), and 3.4% (18/529), respectively. Mutations of NRAS, KRAS, and PTPN11 were mutually exclusive with rare exception, including 4 co-occurrence of NRAS and KRAS mutations, and 2 co-existence of KRAS and PTPN11 mutations. Together, 23.0% of B-precursor ALL patients had gene mutations involving RAS signaling pathway. No differences in age, Hb level, WBC or platelet counts were observed in patients with or without NRAS and PTPN11 mutations. The frequency of PTPN11 mutations was significantly higher in girls than in boys (1.4% vs. 6.0%, P = 0.006). Patients with KRAS mutations presented with significantly younger age (P = 0.004) and lower platelet counts (P = 0.007). Only one out of 21BCR-ABL1 ALL had a mutation (NRAS) in RAS pathway. ETV6/RUNX1 was associated with a lower frequency of NRAS mutations (2.2% vs. 12.3%, P = 0.002) and a trend of less PTPN11 mutations (0% vs. 4.1%, P = 0.053); none of patients with TCF3/PBX1 had KRAS mutation (P = 0.024) whereas 2 of the 3 hypodiploid ALL had KRAS mutations (P = 0.028); KRAS mutations occurred more frequently in patients with MLL rearranged (23.5% vs. 9.2%, P = 0.014, but the difference was not significant if we excluded infant ALL (n = 30) (20% vs. 8.7%, P = 0.223). NRAS mutations were more commonly detected in hyperdiploid ALL (18.0% vs. 9.5%, P = 0.069). Patients without specific genetic/cytogenetic subtypes had a significantly lower frequency of NRAS mutations as compared to those without any of these recurrent genetic abnormalities (7.5% vs. 13.2%, P = 0.048) and a higher rate of PTPN11 mutations (5.0% vs. 1.6%, P = 0.051). There were no differences in 5-year EFS and OS with regard to mutational status of NRAS (70.7% vs. 79.0%, P = 0.575; 89.6% vs. 82.3%, P = 0.863, respectively) and of PTPN11 (80.8% vs. 77.7%, P = 0.490; 90.0% vs. 82.2%, P = 0.317, respectively). KRAS mutations were associated with inferior outcomes (66.0% vs. 79.7%, P = 0.039 for EFS and 74.8% vs. 84.0%, P = 0.058 for OS) but there was no difference in non-infant ALL (P = 0.381 for EFS and P = 0.635 for OS).
Conclusion
Patients with recurrent genetic abnormalities had rare occurrence of RAS pathway mutations in non-infant pediatric B-precursor ALL. NRAS mutations were more frequently detected in patients with hyperdiploidy, whereas KRAS mutations were highly associated with infant ALL with MLL rearranged. (Grants support: MMH-E-99009, MOST103-2314-B-195-008-MY3, MOST104-2314-B-182-032-MY3, OMRPG3C0021 and grant from Terry Fox Foundation)
Session topic: Acute lymphoblastic leukemia - Biology 2
Keyword(s): B cell acute lymphoblastic leukemia, Cytogenetic abnormalities, PTPN11, Ras
Abstract: P163
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
The activating mutations in RAS signaling pathway including NRAS, KRAS and PTPN11 genes have been described in B-precursor acute lymphoblastic leukemia (ALL). However, the correlation of RAS pathway gene mutations with recurrent genetic abnormalities was not addressed.
Aims
We aimed to investigate the frequencies, and the association with genetic/cytogenetic abnormalities as well as prognostic relevance of RAS pathway mutations in Taiwanese children with B-precursor ALL, the largest cohort in Asians.
Methods
Between 1995 and 2012, bone marrow samples at diagnosis from 538 children were studied. Mutations at codons 12, 13, and 61 in exons 1 and 2 of NRAS and KRAS genes, as well as the entire coding region of PTPN11 were analyzed using PCR-based assay followed by direct sequencing. The mutational status of each gene was correlated with the clinico-hematological features, recurrent genetic abnormalities, and outcomes for those treated with TPOG-ALL-2002 protocol (n = 348).
Results
The frequencies of NRAS, KRAS, and PTPN11 mutations were 10.5% (56/533), 10.1% (54/533), and 3.4% (18/529), respectively. Mutations of NRAS, KRAS, and PTPN11 were mutually exclusive with rare exception, including 4 co-occurrence of NRAS and KRAS mutations, and 2 co-existence of KRAS and PTPN11 mutations. Together, 23.0% of B-precursor ALL patients had gene mutations involving RAS signaling pathway. No differences in age, Hb level, WBC or platelet counts were observed in patients with or without NRAS and PTPN11 mutations. The frequency of PTPN11 mutations was significantly higher in girls than in boys (1.4% vs. 6.0%, P = 0.006). Patients with KRAS mutations presented with significantly younger age (P = 0.004) and lower platelet counts (P = 0.007). Only one out of 21BCR-ABL1 ALL had a mutation (NRAS) in RAS pathway. ETV6/RUNX1 was associated with a lower frequency of NRAS mutations (2.2% vs. 12.3%, P = 0.002) and a trend of less PTPN11 mutations (0% vs. 4.1%, P = 0.053); none of patients with TCF3/PBX1 had KRAS mutation (P = 0.024) whereas 2 of the 3 hypodiploid ALL had KRAS mutations (P = 0.028); KRAS mutations occurred more frequently in patients with MLL rearranged (23.5% vs. 9.2%, P = 0.014, but the difference was not significant if we excluded infant ALL (n = 30) (20% vs. 8.7%, P = 0.223). NRAS mutations were more commonly detected in hyperdiploid ALL (18.0% vs. 9.5%, P = 0.069). Patients without specific genetic/cytogenetic subtypes had a significantly lower frequency of NRAS mutations as compared to those without any of these recurrent genetic abnormalities (7.5% vs. 13.2%, P = 0.048) and a higher rate of PTPN11 mutations (5.0% vs. 1.6%, P = 0.051). There were no differences in 5-year EFS and OS with regard to mutational status of NRAS (70.7% vs. 79.0%, P = 0.575; 89.6% vs. 82.3%, P = 0.863, respectively) and of PTPN11 (80.8% vs. 77.7%, P = 0.490; 90.0% vs. 82.2%, P = 0.317, respectively). KRAS mutations were associated with inferior outcomes (66.0% vs. 79.7%, P = 0.039 for EFS and 74.8% vs. 84.0%, P = 0.058 for OS) but there was no difference in non-infant ALL (P = 0.381 for EFS and P = 0.635 for OS).
Conclusion
Patients with recurrent genetic abnormalities had rare occurrence of RAS pathway mutations in non-infant pediatric B-precursor ALL. NRAS mutations were more frequently detected in patients with hyperdiploidy, whereas KRAS mutations were highly associated with infant ALL with MLL rearranged. (Grants support: MMH-E-99009, MOST103-2314-B-195-008-MY3, MOST104-2314-B-182-032-MY3, OMRPG3C0021 and grant from Terry Fox Foundation)
Session topic: Acute lymphoblastic leukemia - Biology 2
Keyword(s): B cell acute lymphoblastic leukemia, Cytogenetic abnormalities, PTPN11, Ras
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
The activating mutations in RAS signaling pathway including NRAS, KRAS and PTPN11 genes have been described in B-precursor acute lymphoblastic leukemia (ALL). However, the correlation of RAS pathway gene mutations with recurrent genetic abnormalities was not addressed.
Aims
We aimed to investigate the frequencies, and the association with genetic/cytogenetic abnormalities as well as prognostic relevance of RAS pathway mutations in Taiwanese children with B-precursor ALL, the largest cohort in Asians.
Methods
Between 1995 and 2012, bone marrow samples at diagnosis from 538 children were studied. Mutations at codons 12, 13, and 61 in exons 1 and 2 of NRAS and KRAS genes, as well as the entire coding region of PTPN11 were analyzed using PCR-based assay followed by direct sequencing. The mutational status of each gene was correlated with the clinico-hematological features, recurrent genetic abnormalities, and outcomes for those treated with TPOG-ALL-2002 protocol (n = 348).
Results
The frequencies of NRAS, KRAS, and PTPN11 mutations were 10.5% (56/533), 10.1% (54/533), and 3.4% (18/529), respectively. Mutations of NRAS, KRAS, and PTPN11 were mutually exclusive with rare exception, including 4 co-occurrence of NRAS and KRAS mutations, and 2 co-existence of KRAS and PTPN11 mutations. Together, 23.0% of B-precursor ALL patients had gene mutations involving RAS signaling pathway. No differences in age, Hb level, WBC or platelet counts were observed in patients with or without NRAS and PTPN11 mutations. The frequency of PTPN11 mutations was significantly higher in girls than in boys (1.4% vs. 6.0%, P = 0.006). Patients with KRAS mutations presented with significantly younger age (P = 0.004) and lower platelet counts (P = 0.007). Only one out of 21BCR-ABL1 ALL had a mutation (NRAS) in RAS pathway. ETV6/RUNX1 was associated with a lower frequency of NRAS mutations (2.2% vs. 12.3%, P = 0.002) and a trend of less PTPN11 mutations (0% vs. 4.1%, P = 0.053); none of patients with TCF3/PBX1 had KRAS mutation (P = 0.024) whereas 2 of the 3 hypodiploid ALL had KRAS mutations (P = 0.028); KRAS mutations occurred more frequently in patients with MLL rearranged (23.5% vs. 9.2%, P = 0.014, but the difference was not significant if we excluded infant ALL (n = 30) (20% vs. 8.7%, P = 0.223). NRAS mutations were more commonly detected in hyperdiploid ALL (18.0% vs. 9.5%, P = 0.069). Patients without specific genetic/cytogenetic subtypes had a significantly lower frequency of NRAS mutations as compared to those without any of these recurrent genetic abnormalities (7.5% vs. 13.2%, P = 0.048) and a higher rate of PTPN11 mutations (5.0% vs. 1.6%, P = 0.051). There were no differences in 5-year EFS and OS with regard to mutational status of NRAS (70.7% vs. 79.0%, P = 0.575; 89.6% vs. 82.3%, P = 0.863, respectively) and of PTPN11 (80.8% vs. 77.7%, P = 0.490; 90.0% vs. 82.2%, P = 0.317, respectively). KRAS mutations were associated with inferior outcomes (66.0% vs. 79.7%, P = 0.039 for EFS and 74.8% vs. 84.0%, P = 0.058 for OS) but there was no difference in non-infant ALL (P = 0.381 for EFS and P = 0.635 for OS).
Conclusion
Patients with recurrent genetic abnormalities had rare occurrence of RAS pathway mutations in non-infant pediatric B-precursor ALL. NRAS mutations were more frequently detected in patients with hyperdiploidy, whereas KRAS mutations were highly associated with infant ALL with MLL rearranged. (Grants support: MMH-E-99009, MOST103-2314-B-195-008-MY3, MOST104-2314-B-182-032-MY3, OMRPG3C0021 and grant from Terry Fox Foundation)
Session topic: Acute lymphoblastic leukemia - Biology 2
Keyword(s): B cell acute lymphoblastic leukemia, Cytogenetic abnormalities, PTPN11, Ras
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