PREVALENCE AND DYNAMICS OF LEUKEMIA-ASSOCIATED MUTATIONS IN ELDERLY INDIVIDUALS WITHOUT HEMATOLOGIC DISORDERS
(Abstract release date: 05/19/16)
EHA Library. Ernst T. 06/09/16; 132740; E1191
Dr. Thomas Ernst
Contributions
Contributions
Abstract
Abstract: E1191
Type: Eposter Presentation
Background
Aging of the hematopoietic system is accompanied by an increased incidence of myeloid disorders such as myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Recent data indicates that aberrations in the aged hematopoietic stem cell (HSC) compartment lead to maintenance or expansion of myeloid cells, while the number of lymphoid progenitors stagnates or declines. HSCs may be particularly predisposed to acquiring genetic aberrations since they are the only persistent cells of the blood system. Such mutations may provide enhanced survival, proliferation and self-renewal capabilities, and lead to the propagation of a cell clone.
Aims
Clonal hematopoiesis is frequently observed in elderly people and may represent a premalignant condition. Clonal HSCs acquiring additional mutations may then transform to cancer cells and give rise to a number of myeloid disorders and leukemia. Evidence suggests that genetic alterations found in patients with myeloid malignancies may also be causative for induction of clonal hematopoiesis. Given these circumstances, discrimination between age-associated and leukemia-associated mutations is of major clinical importance, with potential applications in future prevention, therapy and prognosis.
Methods
In order to investigate the prevalence and dynamics of genetic alterations among elderly individuals without hematologic/oncologic disorders, genotyping of the 30 most commonly mutated leukemia-associated genes was performed. For this purpose peripheral blood DNA and buccal cells from a cohort of 50 elderly people (29 women; median age 84 years; range 80-90 years) were collected and analyzed by targeted deep next-generation sequencing (NGS). All mutations were validated in separate runs using genomic DNA isolated from leukocytes and buccal cells to confirm the somatic origin of mutations.
Results
A total of 16 somatic mutations in leukemia-associated genes were identified in 13 of 50 (26%) hematologically normal elderly individuals. One subject presented with two, another subject with three different mutations. Ten of 16 mutations (63%) affected epigenetic modifier genes (DNMT3A, n=8; TET2, n=1; IDH2, n=1). Four somatic mutations affected genes involved in the RNA splicing machinery (SRSF2, n=2; SF3B1, n=1; U2AF1, n=1). Mutations in TP53 and NRAS were identified in two individuals. All but one mutation were missense mutations with cytosine to thymine transitions being the most common base pair change (n=7). Mutations occurred at low variant allele frequencies (VAF) with a median of 11.7% (range: 1.0% to 30.7%) indicating that mutations were presented in only a subset of blood cells. During a 2-year follow-up observation two subjects with mutations in splicing factor genes died, one subject with an SF3B1 mutation developed pancreatic cancer, the other subject harbored a U2AF1 mutation and died due to a stroke. All other individuals with mutations are alive without any evidence for a hematologic or oncologic disorder. Mutation kinetics remained virtually stable over two years as measured by targeted NGS (median VAF 13.1%, range 1.0% to 35.3%).
Conclusion
These findings indicate that the appearance of low-level clones with mutations in epigenetic regulator genes and the RNA splicing machinery is a common age-associated phenomenon which may represent a premalignant condition in the development of hematologic cancers and may also predispose to other aging associated disorders. The question why these subclones are selected in the elderly but apparently enter a stage of clonal size stability without further selection in healthy elderly in contrast to patients with myeloid disorders is of particular interest and needs further investigation.
Session topic: E-poster
Keyword(s): Elderly, Epigenetic, MDS/AML, Mutation
Type: Eposter Presentation
Background
Aging of the hematopoietic system is accompanied by an increased incidence of myeloid disorders such as myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Recent data indicates that aberrations in the aged hematopoietic stem cell (HSC) compartment lead to maintenance or expansion of myeloid cells, while the number of lymphoid progenitors stagnates or declines. HSCs may be particularly predisposed to acquiring genetic aberrations since they are the only persistent cells of the blood system. Such mutations may provide enhanced survival, proliferation and self-renewal capabilities, and lead to the propagation of a cell clone.
Aims
Clonal hematopoiesis is frequently observed in elderly people and may represent a premalignant condition. Clonal HSCs acquiring additional mutations may then transform to cancer cells and give rise to a number of myeloid disorders and leukemia. Evidence suggests that genetic alterations found in patients with myeloid malignancies may also be causative for induction of clonal hematopoiesis. Given these circumstances, discrimination between age-associated and leukemia-associated mutations is of major clinical importance, with potential applications in future prevention, therapy and prognosis.
Methods
In order to investigate the prevalence and dynamics of genetic alterations among elderly individuals without hematologic/oncologic disorders, genotyping of the 30 most commonly mutated leukemia-associated genes was performed. For this purpose peripheral blood DNA and buccal cells from a cohort of 50 elderly people (29 women; median age 84 years; range 80-90 years) were collected and analyzed by targeted deep next-generation sequencing (NGS). All mutations were validated in separate runs using genomic DNA isolated from leukocytes and buccal cells to confirm the somatic origin of mutations.
Results
A total of 16 somatic mutations in leukemia-associated genes were identified in 13 of 50 (26%) hematologically normal elderly individuals. One subject presented with two, another subject with three different mutations. Ten of 16 mutations (63%) affected epigenetic modifier genes (DNMT3A, n=8; TET2, n=1; IDH2, n=1). Four somatic mutations affected genes involved in the RNA splicing machinery (SRSF2, n=2; SF3B1, n=1; U2AF1, n=1). Mutations in TP53 and NRAS were identified in two individuals. All but one mutation were missense mutations with cytosine to thymine transitions being the most common base pair change (n=7). Mutations occurred at low variant allele frequencies (VAF) with a median of 11.7% (range: 1.0% to 30.7%) indicating that mutations were presented in only a subset of blood cells. During a 2-year follow-up observation two subjects with mutations in splicing factor genes died, one subject with an SF3B1 mutation developed pancreatic cancer, the other subject harbored a U2AF1 mutation and died due to a stroke. All other individuals with mutations are alive without any evidence for a hematologic or oncologic disorder. Mutation kinetics remained virtually stable over two years as measured by targeted NGS (median VAF 13.1%, range 1.0% to 35.3%).
Conclusion
These findings indicate that the appearance of low-level clones with mutations in epigenetic regulator genes and the RNA splicing machinery is a common age-associated phenomenon which may represent a premalignant condition in the development of hematologic cancers and may also predispose to other aging associated disorders. The question why these subclones are selected in the elderly but apparently enter a stage of clonal size stability without further selection in healthy elderly in contrast to patients with myeloid disorders is of particular interest and needs further investigation.
Session topic: E-poster
Keyword(s): Elderly, Epigenetic, MDS/AML, Mutation
Abstract: E1191
Type: Eposter Presentation
Background
Aging of the hematopoietic system is accompanied by an increased incidence of myeloid disorders such as myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Recent data indicates that aberrations in the aged hematopoietic stem cell (HSC) compartment lead to maintenance or expansion of myeloid cells, while the number of lymphoid progenitors stagnates or declines. HSCs may be particularly predisposed to acquiring genetic aberrations since they are the only persistent cells of the blood system. Such mutations may provide enhanced survival, proliferation and self-renewal capabilities, and lead to the propagation of a cell clone.
Aims
Clonal hematopoiesis is frequently observed in elderly people and may represent a premalignant condition. Clonal HSCs acquiring additional mutations may then transform to cancer cells and give rise to a number of myeloid disorders and leukemia. Evidence suggests that genetic alterations found in patients with myeloid malignancies may also be causative for induction of clonal hematopoiesis. Given these circumstances, discrimination between age-associated and leukemia-associated mutations is of major clinical importance, with potential applications in future prevention, therapy and prognosis.
Methods
In order to investigate the prevalence and dynamics of genetic alterations among elderly individuals without hematologic/oncologic disorders, genotyping of the 30 most commonly mutated leukemia-associated genes was performed. For this purpose peripheral blood DNA and buccal cells from a cohort of 50 elderly people (29 women; median age 84 years; range 80-90 years) were collected and analyzed by targeted deep next-generation sequencing (NGS). All mutations were validated in separate runs using genomic DNA isolated from leukocytes and buccal cells to confirm the somatic origin of mutations.
Results
A total of 16 somatic mutations in leukemia-associated genes were identified in 13 of 50 (26%) hematologically normal elderly individuals. One subject presented with two, another subject with three different mutations. Ten of 16 mutations (63%) affected epigenetic modifier genes (DNMT3A, n=8; TET2, n=1; IDH2, n=1). Four somatic mutations affected genes involved in the RNA splicing machinery (SRSF2, n=2; SF3B1, n=1; U2AF1, n=1). Mutations in TP53 and NRAS were identified in two individuals. All but one mutation were missense mutations with cytosine to thymine transitions being the most common base pair change (n=7). Mutations occurred at low variant allele frequencies (VAF) with a median of 11.7% (range: 1.0% to 30.7%) indicating that mutations were presented in only a subset of blood cells. During a 2-year follow-up observation two subjects with mutations in splicing factor genes died, one subject with an SF3B1 mutation developed pancreatic cancer, the other subject harbored a U2AF1 mutation and died due to a stroke. All other individuals with mutations are alive without any evidence for a hematologic or oncologic disorder. Mutation kinetics remained virtually stable over two years as measured by targeted NGS (median VAF 13.1%, range 1.0% to 35.3%).
Conclusion
These findings indicate that the appearance of low-level clones with mutations in epigenetic regulator genes and the RNA splicing machinery is a common age-associated phenomenon which may represent a premalignant condition in the development of hematologic cancers and may also predispose to other aging associated disorders. The question why these subclones are selected in the elderly but apparently enter a stage of clonal size stability without further selection in healthy elderly in contrast to patients with myeloid disorders is of particular interest and needs further investigation.
Session topic: E-poster
Keyword(s): Elderly, Epigenetic, MDS/AML, Mutation
Type: Eposter Presentation
Background
Aging of the hematopoietic system is accompanied by an increased incidence of myeloid disorders such as myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Recent data indicates that aberrations in the aged hematopoietic stem cell (HSC) compartment lead to maintenance or expansion of myeloid cells, while the number of lymphoid progenitors stagnates or declines. HSCs may be particularly predisposed to acquiring genetic aberrations since they are the only persistent cells of the blood system. Such mutations may provide enhanced survival, proliferation and self-renewal capabilities, and lead to the propagation of a cell clone.
Aims
Clonal hematopoiesis is frequently observed in elderly people and may represent a premalignant condition. Clonal HSCs acquiring additional mutations may then transform to cancer cells and give rise to a number of myeloid disorders and leukemia. Evidence suggests that genetic alterations found in patients with myeloid malignancies may also be causative for induction of clonal hematopoiesis. Given these circumstances, discrimination between age-associated and leukemia-associated mutations is of major clinical importance, with potential applications in future prevention, therapy and prognosis.
Methods
In order to investigate the prevalence and dynamics of genetic alterations among elderly individuals without hematologic/oncologic disorders, genotyping of the 30 most commonly mutated leukemia-associated genes was performed. For this purpose peripheral blood DNA and buccal cells from a cohort of 50 elderly people (29 women; median age 84 years; range 80-90 years) were collected and analyzed by targeted deep next-generation sequencing (NGS). All mutations were validated in separate runs using genomic DNA isolated from leukocytes and buccal cells to confirm the somatic origin of mutations.
Results
A total of 16 somatic mutations in leukemia-associated genes were identified in 13 of 50 (26%) hematologically normal elderly individuals. One subject presented with two, another subject with three different mutations. Ten of 16 mutations (63%) affected epigenetic modifier genes (DNMT3A, n=8; TET2, n=1; IDH2, n=1). Four somatic mutations affected genes involved in the RNA splicing machinery (SRSF2, n=2; SF3B1, n=1; U2AF1, n=1). Mutations in TP53 and NRAS were identified in two individuals. All but one mutation were missense mutations with cytosine to thymine transitions being the most common base pair change (n=7). Mutations occurred at low variant allele frequencies (VAF) with a median of 11.7% (range: 1.0% to 30.7%) indicating that mutations were presented in only a subset of blood cells. During a 2-year follow-up observation two subjects with mutations in splicing factor genes died, one subject with an SF3B1 mutation developed pancreatic cancer, the other subject harbored a U2AF1 mutation and died due to a stroke. All other individuals with mutations are alive without any evidence for a hematologic or oncologic disorder. Mutation kinetics remained virtually stable over two years as measured by targeted NGS (median VAF 13.1%, range 1.0% to 35.3%).
Conclusion
These findings indicate that the appearance of low-level clones with mutations in epigenetic regulator genes and the RNA splicing machinery is a common age-associated phenomenon which may represent a premalignant condition in the development of hematologic cancers and may also predispose to other aging associated disorders. The question why these subclones are selected in the elderly but apparently enter a stage of clonal size stability without further selection in healthy elderly in contrast to patients with myeloid disorders is of particular interest and needs further investigation.
Session topic: E-poster
Keyword(s): Elderly, Epigenetic, MDS/AML, Mutation
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