Abstract
Therapy-related myeloid neoplasms (t-MN) may occur as a late effect of cytotoxic therapy for a primary malignancy or autoimmune diseases in susceptible individuals. We studied the development of somatic mutations in t-MN, using a collection of follow-up samples from 14 patients with a primary hematologic malignancy, who developed a secondary leukemia (13 t-MN and 1 t-acute lymphoblastic leukemia), at a median latency of 73 months (range 18-108) from primary cancer diagnosis.Using Sanger and next generation sequencing (NGS) approaches we identified 8 mutations (IDH1 R132H, ASXL1 Y591*, ASXL1 S689*, ASXL1 R693*, SRSF2 P95H, SF3B1 K700E, SETBP1 G870R and TP53 Y220C) in seven of thirteen t-MN patients (54%), whereas the t-ALL patient had a t(4,11) translocation, resulting in the KMT2A/AFF1 fusion gene. These mutations were then tracked backwards in marrow samples preceding secondary leukemia occurrence, using pyrosequencing and a NGS protocol that allows the detection of low variant allele frequencies (≥0.1%).Somatic mutations were detectable in the BM harvested at the primary diagnosis, prior to any cytotoxic treatment in three patients, while they were not detectable and apparently acquired by the t-MN clone in five patients.These data show that clonal evolution in t-MN is heterogeneous, with some somatic mutations preceding cytotoxic treatment and possibly favoring leukemic development.
Highlights
Therapy-related myeloid neoplasms include myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) occurring as a late effect of chemoand/or radiotherapy for a primary malignancy or an autoimmune disease and have been included in the WHO classification of acute leukemia [1,2,3]
We studied the development of somatic mutations in Therapy-related myeloid neoplasms (t-MN), using a collection of followup samples from 14 patients with a primary hematologic malignancy, who developed a secondary leukemia (13 t-MN and 1 t-acute lymphoblastic leukemia), at a median latency of 73 months from primary cancer diagnosis
Using Sanger and generation sequencing (NGS) approaches we identified 8 mutations (IDH1 R132H, ASXL1 Y591*, ASXL1 S689*, ASXL1 R693*, SRSF2 P95H, SF3B1 K700E, SETBP1 G870R and TP53 Y220C) in seven of thirteen t-MN patients (54%), whereas the therapy-related acute lymphoblastic leukemia (t-ALL) patient had a t(4,11) translocation, resulting in the KMT2A/ AFF1 fusion gene
Summary
Therapy-related myeloid neoplasms include myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) occurring as a late effect of chemoand/or radiotherapy for a primary malignancy or an autoimmune disease and have been included in the WHO classification of acute leukemia [1,2,3]. On the other hand, using a modified generation sequencing (NGS) protocol that allows the detection of very low TP53 variant allele frequencies, the authors of this study found the same TP53 mutation identified at the time of t-MN diagnosis in bone marrow (BM) samples collected prior to any chemotherapy. In this line, somatic mutations in genes associated to hematological malignancies have been found in the peripheral blood of elderly otherwise healthy individuals, suggesting that mutations can naturally occur in hematopoietic cells [14,15]
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