DYNAMICS OF CLONAL EVOLUTION IN MYELODYSPLASTIC SYNDROMES.
(Abstract release date: 05/19/16)
EHA Library. Makishima H. 06/11/16; 135198; S442
Assoc. Prof. Hideki Makishima
Contributions
Contributions
Abstract
Abstract: S442
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 11:30 - 11:45
Location: Hall C11
Background
The development and progression of cancer are shaped by dynamic alterations of clonal architecture, characterization of which in terms of gene mutations is essential for the understanding of the pathogenesis of cancer. However, the clonal architecture in myelodysplastic syndromes (MDS) has been only inferred from the allelic burden of a limited number of driver mutations at a single time point. Comprehensive mutation profiling of serial samples has been performed only for a small number of patients.
Aims
We aimed to delineate the impact of clonal dynamics on disease phenotypes, progression to secondary acute myeloid leukemia (sAML), and clinical outcomes in a large cohort of fully genotyped MDS patients.
Methods
Clonal architecture and dynamics were investigated by whole exome sequencing (WES) and/or targeted sequencing of 779 patients with MDS and sAML, of whom 97 were analyzed longitudinally. Combined with published data sets (N=2,133), the data were also used to interrogate differential roles of driver mutations in disease progression.
Results
Higher-risk MDS was characterized by a higher number of mutations with increasing diversity and a larger clone size. The number of cases with heterogeneity was significantly higher in sAML compared to lower-risk MDS (P = 0.03). In WES analysis of serial samples, evolution of a new dominant clone that swept out other subclones was common during disease progression and frequently accompanied by newly emerging subclones. Leukemic transformation was heralded by acquisition of new mutations in most cases without clone sweeping.To clarify the relationship between driver mutations and disease progression or phenotype, we compared frequencies of major driver mutations between disease subtypes within a large cohort of patients. In total, data from samples with lower- (n=1,157) and higher-risk (n=672) MDS, as well as sAML (n=304), were subjected to analysis of 27 driver genes mutated in more than 2% of the entire cohort. Mutations in genes designated as Type-1 (FLT3, PTPN11, IDH1, CBL, and NRAS) were significantly enriched in sAML compared to higher-risk MDS. When compared between higher- and lower-risk MDS, we observed a skewed enrichment of certain driver mutations in higher-risk MDS, designated here as Type-2 (TP53, GATA2, RUNX1, IDH2, STAG2, ASXL1, and NPM1). In longitudinal samples, Type-1 mutations were more likely to be newly acquired or to increase in clone size (P = 1.94×10-4, trend test). In contrast, more Type-2 and other mutations decreased in their clone size or were even lost in the second sampling. Patients with Type-1 mutations (Group-I) had a significantly shorter time to progression to sAML compared to other patients (hazard ratio (HR) = 5.7, 95% confidence interval (CI) = 3.4−9.6; P < 0.001). Time to sAML in Group-I patients was also significantly shorter than that in patients who had Type-2 mutations but lacked Type-1 mutations (Group-II) (HR = 3.0, 95% CI = 1.7−5.4; P < 0.001). Despite the significant difference in the rate of progression to sAML between patients in Group-I and Group-II, both had a similar overall survival. Accordingly, in Group-II patients more deaths occurred before progression to sAML, compared to Group-I patients.
Conclusion
Dynamics of clonal architecture strongly correlates with distinct types of mutations, which are significantly associated with leukemia-free survival and non-leukemia death, suggesting that screening of these specific mutations might be useful for the prediction of clinical outcome.
Session topic: Myelodysplastic syndromes - Biology
Keyword(s): Acute myeloid leukemia, Mutation status, Myelodysplasia, Secondary
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 11:30 - 11:45
Location: Hall C11
Background
The development and progression of cancer are shaped by dynamic alterations of clonal architecture, characterization of which in terms of gene mutations is essential for the understanding of the pathogenesis of cancer. However, the clonal architecture in myelodysplastic syndromes (MDS) has been only inferred from the allelic burden of a limited number of driver mutations at a single time point. Comprehensive mutation profiling of serial samples has been performed only for a small number of patients.
Aims
We aimed to delineate the impact of clonal dynamics on disease phenotypes, progression to secondary acute myeloid leukemia (sAML), and clinical outcomes in a large cohort of fully genotyped MDS patients.
Methods
Clonal architecture and dynamics were investigated by whole exome sequencing (WES) and/or targeted sequencing of 779 patients with MDS and sAML, of whom 97 were analyzed longitudinally. Combined with published data sets (N=2,133), the data were also used to interrogate differential roles of driver mutations in disease progression.
Results
Higher-risk MDS was characterized by a higher number of mutations with increasing diversity and a larger clone size. The number of cases with heterogeneity was significantly higher in sAML compared to lower-risk MDS (P = 0.03). In WES analysis of serial samples, evolution of a new dominant clone that swept out other subclones was common during disease progression and frequently accompanied by newly emerging subclones. Leukemic transformation was heralded by acquisition of new mutations in most cases without clone sweeping.To clarify the relationship between driver mutations and disease progression or phenotype, we compared frequencies of major driver mutations between disease subtypes within a large cohort of patients. In total, data from samples with lower- (n=1,157) and higher-risk (n=672) MDS, as well as sAML (n=304), were subjected to analysis of 27 driver genes mutated in more than 2% of the entire cohort. Mutations in genes designated as Type-1 (FLT3, PTPN11, IDH1, CBL, and NRAS) were significantly enriched in sAML compared to higher-risk MDS. When compared between higher- and lower-risk MDS, we observed a skewed enrichment of certain driver mutations in higher-risk MDS, designated here as Type-2 (TP53, GATA2, RUNX1, IDH2, STAG2, ASXL1, and NPM1). In longitudinal samples, Type-1 mutations were more likely to be newly acquired or to increase in clone size (P = 1.94×10-4, trend test). In contrast, more Type-2 and other mutations decreased in their clone size or were even lost in the second sampling. Patients with Type-1 mutations (Group-I) had a significantly shorter time to progression to sAML compared to other patients (hazard ratio (HR) = 5.7, 95% confidence interval (CI) = 3.4−9.6; P < 0.001). Time to sAML in Group-I patients was also significantly shorter than that in patients who had Type-2 mutations but lacked Type-1 mutations (Group-II) (HR = 3.0, 95% CI = 1.7−5.4; P < 0.001). Despite the significant difference in the rate of progression to sAML between patients in Group-I and Group-II, both had a similar overall survival. Accordingly, in Group-II patients more deaths occurred before progression to sAML, compared to Group-I patients.
Conclusion
Dynamics of clonal architecture strongly correlates with distinct types of mutations, which are significantly associated with leukemia-free survival and non-leukemia death, suggesting that screening of these specific mutations might be useful for the prediction of clinical outcome.
Session topic: Myelodysplastic syndromes - Biology
Keyword(s): Acute myeloid leukemia, Mutation status, Myelodysplasia, Secondary
Abstract: S442
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 11:30 - 11:45
Location: Hall C11
Background
The development and progression of cancer are shaped by dynamic alterations of clonal architecture, characterization of which in terms of gene mutations is essential for the understanding of the pathogenesis of cancer. However, the clonal architecture in myelodysplastic syndromes (MDS) has been only inferred from the allelic burden of a limited number of driver mutations at a single time point. Comprehensive mutation profiling of serial samples has been performed only for a small number of patients.
Aims
We aimed to delineate the impact of clonal dynamics on disease phenotypes, progression to secondary acute myeloid leukemia (sAML), and clinical outcomes in a large cohort of fully genotyped MDS patients.
Methods
Clonal architecture and dynamics were investigated by whole exome sequencing (WES) and/or targeted sequencing of 779 patients with MDS and sAML, of whom 97 were analyzed longitudinally. Combined with published data sets (N=2,133), the data were also used to interrogate differential roles of driver mutations in disease progression.
Results
Higher-risk MDS was characterized by a higher number of mutations with increasing diversity and a larger clone size. The number of cases with heterogeneity was significantly higher in sAML compared to lower-risk MDS (P = 0.03). In WES analysis of serial samples, evolution of a new dominant clone that swept out other subclones was common during disease progression and frequently accompanied by newly emerging subclones. Leukemic transformation was heralded by acquisition of new mutations in most cases without clone sweeping.To clarify the relationship between driver mutations and disease progression or phenotype, we compared frequencies of major driver mutations between disease subtypes within a large cohort of patients. In total, data from samples with lower- (n=1,157) and higher-risk (n=672) MDS, as well as sAML (n=304), were subjected to analysis of 27 driver genes mutated in more than 2% of the entire cohort. Mutations in genes designated as Type-1 (FLT3, PTPN11, IDH1, CBL, and NRAS) were significantly enriched in sAML compared to higher-risk MDS. When compared between higher- and lower-risk MDS, we observed a skewed enrichment of certain driver mutations in higher-risk MDS, designated here as Type-2 (TP53, GATA2, RUNX1, IDH2, STAG2, ASXL1, and NPM1). In longitudinal samples, Type-1 mutations were more likely to be newly acquired or to increase in clone size (P = 1.94×10-4, trend test). In contrast, more Type-2 and other mutations decreased in their clone size or were even lost in the second sampling. Patients with Type-1 mutations (Group-I) had a significantly shorter time to progression to sAML compared to other patients (hazard ratio (HR) = 5.7, 95% confidence interval (CI) = 3.4−9.6; P < 0.001). Time to sAML in Group-I patients was also significantly shorter than that in patients who had Type-2 mutations but lacked Type-1 mutations (Group-II) (HR = 3.0, 95% CI = 1.7−5.4; P < 0.001). Despite the significant difference in the rate of progression to sAML between patients in Group-I and Group-II, both had a similar overall survival. Accordingly, in Group-II patients more deaths occurred before progression to sAML, compared to Group-I patients.
Conclusion
Dynamics of clonal architecture strongly correlates with distinct types of mutations, which are significantly associated with leukemia-free survival and non-leukemia death, suggesting that screening of these specific mutations might be useful for the prediction of clinical outcome.
Session topic: Myelodysplastic syndromes - Biology
Keyword(s): Acute myeloid leukemia, Mutation status, Myelodysplasia, Secondary
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 11:30 - 11:45
Location: Hall C11
Background
The development and progression of cancer are shaped by dynamic alterations of clonal architecture, characterization of which in terms of gene mutations is essential for the understanding of the pathogenesis of cancer. However, the clonal architecture in myelodysplastic syndromes (MDS) has been only inferred from the allelic burden of a limited number of driver mutations at a single time point. Comprehensive mutation profiling of serial samples has been performed only for a small number of patients.
Aims
We aimed to delineate the impact of clonal dynamics on disease phenotypes, progression to secondary acute myeloid leukemia (sAML), and clinical outcomes in a large cohort of fully genotyped MDS patients.
Methods
Clonal architecture and dynamics were investigated by whole exome sequencing (WES) and/or targeted sequencing of 779 patients with MDS and sAML, of whom 97 were analyzed longitudinally. Combined with published data sets (N=2,133), the data were also used to interrogate differential roles of driver mutations in disease progression.
Results
Higher-risk MDS was characterized by a higher number of mutations with increasing diversity and a larger clone size. The number of cases with heterogeneity was significantly higher in sAML compared to lower-risk MDS (P = 0.03). In WES analysis of serial samples, evolution of a new dominant clone that swept out other subclones was common during disease progression and frequently accompanied by newly emerging subclones. Leukemic transformation was heralded by acquisition of new mutations in most cases without clone sweeping.To clarify the relationship between driver mutations and disease progression or phenotype, we compared frequencies of major driver mutations between disease subtypes within a large cohort of patients. In total, data from samples with lower- (n=1,157) and higher-risk (n=672) MDS, as well as sAML (n=304), were subjected to analysis of 27 driver genes mutated in more than 2% of the entire cohort. Mutations in genes designated as Type-1 (FLT3, PTPN11, IDH1, CBL, and NRAS) were significantly enriched in sAML compared to higher-risk MDS. When compared between higher- and lower-risk MDS, we observed a skewed enrichment of certain driver mutations in higher-risk MDS, designated here as Type-2 (TP53, GATA2, RUNX1, IDH2, STAG2, ASXL1, and NPM1). In longitudinal samples, Type-1 mutations were more likely to be newly acquired or to increase in clone size (P = 1.94×10-4, trend test). In contrast, more Type-2 and other mutations decreased in their clone size or were even lost in the second sampling. Patients with Type-1 mutations (Group-I) had a significantly shorter time to progression to sAML compared to other patients (hazard ratio (HR) = 5.7, 95% confidence interval (CI) = 3.4−9.6; P < 0.001). Time to sAML in Group-I patients was also significantly shorter than that in patients who had Type-2 mutations but lacked Type-1 mutations (Group-II) (HR = 3.0, 95% CI = 1.7−5.4; P < 0.001). Despite the significant difference in the rate of progression to sAML between patients in Group-I and Group-II, both had a similar overall survival. Accordingly, in Group-II patients more deaths occurred before progression to sAML, compared to Group-I patients.
Conclusion
Dynamics of clonal architecture strongly correlates with distinct types of mutations, which are significantly associated with leukemia-free survival and non-leukemia death, suggesting that screening of these specific mutations might be useful for the prediction of clinical outcome.
Session topic: Myelodysplastic syndromes - Biology
Keyword(s): Acute myeloid leukemia, Mutation status, Myelodysplasia, Secondary
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