SPATIAL INTERACTION OF CYTOGENETIC AND MOLECULAR MUTATIONS IN MYELODYSPLASTIC SYNDROMES
(Abstract release date: 05/19/16)
EHA Library. Haase D. 06/09/16; 132748; E1199
Prof. Dr. Detlef Haase
Contributions
Contributions
Abstract
Abstract: E1199
Type: Eposter Presentation
Background
In myelodysplastic syndromes (MDS), several frequent molecular mutations affect the same chromosomal regions as common cytogenetic mutations. These regions are potential targets of total loss of function of cancer-protective genes or could be involved in gain of function of oncogenes. Both alleles could be simultaneously affected by two different mutation types, one allele by a molecular mutation and the second allele by a cytogenetic mutation (deletion, copy number neutral loss of heterozygosity (CN-LOH) and others). Up to now the impact of biallelic mutations composed by a molecular and a cytogenetic mutation on leukemogenesis is unknown in MDS.
Aims
The aim of our study was to identify and to characterize such biallelic mutations (composed by a molecular and a cytogenetic mutation) to delineate the frequency and the potential clinical significance in MDS.
Methods
We included 209 patients in our analysis: 144 proven MDS, 27 suspected MDS with typical genetic aberrations, 9 myelodysplastic/myeloproliferative neoplasms (MSD/MPN), and 29 secondary acute myeloid leukemias (sAML) after MDS. Molecular analysis was done by Sanger sequencing including up to 17 of the most frequently mutated genes in MDS. The basis of cytogenetic analysis was conventional chromosome banding that was complemented by interphase fluorescence in situ hybridization (FISH), multicolor FISH and/or molecular karyotyping (SNP array analysis).
Results
Overall, genetic mutations were detected in 84.7% of patients. Cytogenetics identified mutations in 46.9% and sequencing revealed mutations in 70.8% of patients. In 20 patients (9.6%) a molecular mutation was located in a chromosomal region that was in addition affected by a cytogenetic aberration (assumed to affect the second allele). Such biallelic mutations were more frequent in MDS-RAEB (9/51, 18%), MDS/MPN (2/9, 22%), and sAML (5/29, 17%), but rarer in low-risk MDS (4/93, 4%). The highest frequency of such biallelic mutations was detected in patients with CBL mutations: 2/3 CBL mutations were located within a CN-LOH of 11q. Furthermore, 4/11 patients with EZH2 mutations had a cytogenetic 7q aberration (2x deletion, 2x CN-LOH), 4/13 patients with TP53 mutations additionally showed cytogenetic loss of 17p. We detected two patients with a SRSF2 mutation and a simultaneous isochromosome iso(17q) that results in gain of 17q. Other molecular mutations involved in such biallelic mutations were: SRSF2 (1x CN-LOH), TET2 (2x loss, 1x CN-LOH), DNMT3A (2x CN-LOH), and RUNX1 (2x CN-LOH).
Conclusion
Biallelic mutations composed by a molecular and a cytogenetic mutation affecting the same chromosomal region were recurrently identified in sAML and MDS/MPN in our study but were detected also in low-risk MDS albeit at lower frequency. Co-occurrence of molecular and cytogenetic lesions affecting e.g. TP53/7q, EZH2/7q or CBL/11q suggests individual pathomechanisms resulting in homozygous loss of function of potential tumor suppressor genes. The co-occurrence of activating SRSF2 mutations and iso(17q) or CN-LOH of 17q might have an oncogenic effect. Biallelic mutations could be indicative for a regional genetic instability promoting disease progression. According to the two-hit hypothesis such “composed” biallelic mutations might arise stepwise. Therefore, they could refer to previous genetic evolution and consequently to advanced stages of the disease. Sixteen of the 20 biallelic mutations identified in our study affected patients with high-risk MDS or sAML. Thus, patients with biallelic mutations due to a molecular and a cytogenetic mutation in parallel could be at high risk for further progression of the disease.
Session topic: E-poster
Keyword(s): Cytogenetics, MDS, Mutation
Type: Eposter Presentation
Background
In myelodysplastic syndromes (MDS), several frequent molecular mutations affect the same chromosomal regions as common cytogenetic mutations. These regions are potential targets of total loss of function of cancer-protective genes or could be involved in gain of function of oncogenes. Both alleles could be simultaneously affected by two different mutation types, one allele by a molecular mutation and the second allele by a cytogenetic mutation (deletion, copy number neutral loss of heterozygosity (CN-LOH) and others). Up to now the impact of biallelic mutations composed by a molecular and a cytogenetic mutation on leukemogenesis is unknown in MDS.
Aims
The aim of our study was to identify and to characterize such biallelic mutations (composed by a molecular and a cytogenetic mutation) to delineate the frequency and the potential clinical significance in MDS.
Methods
We included 209 patients in our analysis: 144 proven MDS, 27 suspected MDS with typical genetic aberrations, 9 myelodysplastic/myeloproliferative neoplasms (MSD/MPN), and 29 secondary acute myeloid leukemias (sAML) after MDS. Molecular analysis was done by Sanger sequencing including up to 17 of the most frequently mutated genes in MDS. The basis of cytogenetic analysis was conventional chromosome banding that was complemented by interphase fluorescence in situ hybridization (FISH), multicolor FISH and/or molecular karyotyping (SNP array analysis).
Results
Overall, genetic mutations were detected in 84.7% of patients. Cytogenetics identified mutations in 46.9% and sequencing revealed mutations in 70.8% of patients. In 20 patients (9.6%) a molecular mutation was located in a chromosomal region that was in addition affected by a cytogenetic aberration (assumed to affect the second allele). Such biallelic mutations were more frequent in MDS-RAEB (9/51, 18%), MDS/MPN (2/9, 22%), and sAML (5/29, 17%), but rarer in low-risk MDS (4/93, 4%). The highest frequency of such biallelic mutations was detected in patients with CBL mutations: 2/3 CBL mutations were located within a CN-LOH of 11q. Furthermore, 4/11 patients with EZH2 mutations had a cytogenetic 7q aberration (2x deletion, 2x CN-LOH), 4/13 patients with TP53 mutations additionally showed cytogenetic loss of 17p. We detected two patients with a SRSF2 mutation and a simultaneous isochromosome iso(17q) that results in gain of 17q. Other molecular mutations involved in such biallelic mutations were: SRSF2 (1x CN-LOH), TET2 (2x loss, 1x CN-LOH), DNMT3A (2x CN-LOH), and RUNX1 (2x CN-LOH).
Conclusion
Biallelic mutations composed by a molecular and a cytogenetic mutation affecting the same chromosomal region were recurrently identified in sAML and MDS/MPN in our study but were detected also in low-risk MDS albeit at lower frequency. Co-occurrence of molecular and cytogenetic lesions affecting e.g. TP53/7q, EZH2/7q or CBL/11q suggests individual pathomechanisms resulting in homozygous loss of function of potential tumor suppressor genes. The co-occurrence of activating SRSF2 mutations and iso(17q) or CN-LOH of 17q might have an oncogenic effect. Biallelic mutations could be indicative for a regional genetic instability promoting disease progression. According to the two-hit hypothesis such “composed” biallelic mutations might arise stepwise. Therefore, they could refer to previous genetic evolution and consequently to advanced stages of the disease. Sixteen of the 20 biallelic mutations identified in our study affected patients with high-risk MDS or sAML. Thus, patients with biallelic mutations due to a molecular and a cytogenetic mutation in parallel could be at high risk for further progression of the disease.
Session topic: E-poster
Keyword(s): Cytogenetics, MDS, Mutation
Abstract: E1199
Type: Eposter Presentation
Background
In myelodysplastic syndromes (MDS), several frequent molecular mutations affect the same chromosomal regions as common cytogenetic mutations. These regions are potential targets of total loss of function of cancer-protective genes or could be involved in gain of function of oncogenes. Both alleles could be simultaneously affected by two different mutation types, one allele by a molecular mutation and the second allele by a cytogenetic mutation (deletion, copy number neutral loss of heterozygosity (CN-LOH) and others). Up to now the impact of biallelic mutations composed by a molecular and a cytogenetic mutation on leukemogenesis is unknown in MDS.
Aims
The aim of our study was to identify and to characterize such biallelic mutations (composed by a molecular and a cytogenetic mutation) to delineate the frequency and the potential clinical significance in MDS.
Methods
We included 209 patients in our analysis: 144 proven MDS, 27 suspected MDS with typical genetic aberrations, 9 myelodysplastic/myeloproliferative neoplasms (MSD/MPN), and 29 secondary acute myeloid leukemias (sAML) after MDS. Molecular analysis was done by Sanger sequencing including up to 17 of the most frequently mutated genes in MDS. The basis of cytogenetic analysis was conventional chromosome banding that was complemented by interphase fluorescence in situ hybridization (FISH), multicolor FISH and/or molecular karyotyping (SNP array analysis).
Results
Overall, genetic mutations were detected in 84.7% of patients. Cytogenetics identified mutations in 46.9% and sequencing revealed mutations in 70.8% of patients. In 20 patients (9.6%) a molecular mutation was located in a chromosomal region that was in addition affected by a cytogenetic aberration (assumed to affect the second allele). Such biallelic mutations were more frequent in MDS-RAEB (9/51, 18%), MDS/MPN (2/9, 22%), and sAML (5/29, 17%), but rarer in low-risk MDS (4/93, 4%). The highest frequency of such biallelic mutations was detected in patients with CBL mutations: 2/3 CBL mutations were located within a CN-LOH of 11q. Furthermore, 4/11 patients with EZH2 mutations had a cytogenetic 7q aberration (2x deletion, 2x CN-LOH), 4/13 patients with TP53 mutations additionally showed cytogenetic loss of 17p. We detected two patients with a SRSF2 mutation and a simultaneous isochromosome iso(17q) that results in gain of 17q. Other molecular mutations involved in such biallelic mutations were: SRSF2 (1x CN-LOH), TET2 (2x loss, 1x CN-LOH), DNMT3A (2x CN-LOH), and RUNX1 (2x CN-LOH).
Conclusion
Biallelic mutations composed by a molecular and a cytogenetic mutation affecting the same chromosomal region were recurrently identified in sAML and MDS/MPN in our study but were detected also in low-risk MDS albeit at lower frequency. Co-occurrence of molecular and cytogenetic lesions affecting e.g. TP53/7q, EZH2/7q or CBL/11q suggests individual pathomechanisms resulting in homozygous loss of function of potential tumor suppressor genes. The co-occurrence of activating SRSF2 mutations and iso(17q) or CN-LOH of 17q might have an oncogenic effect. Biallelic mutations could be indicative for a regional genetic instability promoting disease progression. According to the two-hit hypothesis such “composed” biallelic mutations might arise stepwise. Therefore, they could refer to previous genetic evolution and consequently to advanced stages of the disease. Sixteen of the 20 biallelic mutations identified in our study affected patients with high-risk MDS or sAML. Thus, patients with biallelic mutations due to a molecular and a cytogenetic mutation in parallel could be at high risk for further progression of the disease.
Session topic: E-poster
Keyword(s): Cytogenetics, MDS, Mutation
Type: Eposter Presentation
Background
In myelodysplastic syndromes (MDS), several frequent molecular mutations affect the same chromosomal regions as common cytogenetic mutations. These regions are potential targets of total loss of function of cancer-protective genes or could be involved in gain of function of oncogenes. Both alleles could be simultaneously affected by two different mutation types, one allele by a molecular mutation and the second allele by a cytogenetic mutation (deletion, copy number neutral loss of heterozygosity (CN-LOH) and others). Up to now the impact of biallelic mutations composed by a molecular and a cytogenetic mutation on leukemogenesis is unknown in MDS.
Aims
The aim of our study was to identify and to characterize such biallelic mutations (composed by a molecular and a cytogenetic mutation) to delineate the frequency and the potential clinical significance in MDS.
Methods
We included 209 patients in our analysis: 144 proven MDS, 27 suspected MDS with typical genetic aberrations, 9 myelodysplastic/myeloproliferative neoplasms (MSD/MPN), and 29 secondary acute myeloid leukemias (sAML) after MDS. Molecular analysis was done by Sanger sequencing including up to 17 of the most frequently mutated genes in MDS. The basis of cytogenetic analysis was conventional chromosome banding that was complemented by interphase fluorescence in situ hybridization (FISH), multicolor FISH and/or molecular karyotyping (SNP array analysis).
Results
Overall, genetic mutations were detected in 84.7% of patients. Cytogenetics identified mutations in 46.9% and sequencing revealed mutations in 70.8% of patients. In 20 patients (9.6%) a molecular mutation was located in a chromosomal region that was in addition affected by a cytogenetic aberration (assumed to affect the second allele). Such biallelic mutations were more frequent in MDS-RAEB (9/51, 18%), MDS/MPN (2/9, 22%), and sAML (5/29, 17%), but rarer in low-risk MDS (4/93, 4%). The highest frequency of such biallelic mutations was detected in patients with CBL mutations: 2/3 CBL mutations were located within a CN-LOH of 11q. Furthermore, 4/11 patients with EZH2 mutations had a cytogenetic 7q aberration (2x deletion, 2x CN-LOH), 4/13 patients with TP53 mutations additionally showed cytogenetic loss of 17p. We detected two patients with a SRSF2 mutation and a simultaneous isochromosome iso(17q) that results in gain of 17q. Other molecular mutations involved in such biallelic mutations were: SRSF2 (1x CN-LOH), TET2 (2x loss, 1x CN-LOH), DNMT3A (2x CN-LOH), and RUNX1 (2x CN-LOH).
Conclusion
Biallelic mutations composed by a molecular and a cytogenetic mutation affecting the same chromosomal region were recurrently identified in sAML and MDS/MPN in our study but were detected also in low-risk MDS albeit at lower frequency. Co-occurrence of molecular and cytogenetic lesions affecting e.g. TP53/7q, EZH2/7q or CBL/11q suggests individual pathomechanisms resulting in homozygous loss of function of potential tumor suppressor genes. The co-occurrence of activating SRSF2 mutations and iso(17q) or CN-LOH of 17q might have an oncogenic effect. Biallelic mutations could be indicative for a regional genetic instability promoting disease progression. According to the two-hit hypothesis such “composed” biallelic mutations might arise stepwise. Therefore, they could refer to previous genetic evolution and consequently to advanced stages of the disease. Sixteen of the 20 biallelic mutations identified in our study affected patients with high-risk MDS or sAML. Thus, patients with biallelic mutations due to a molecular and a cytogenetic mutation in parallel could be at high risk for further progression of the disease.
Session topic: E-poster
Keyword(s): Cytogenetics, MDS, Mutation
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