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Oncotarget. 2017 Feb 14;8(7):12031-12040. doi: 10.18632/oncotarget.14509.

Clonal evolution in therapy-related neoplasms.

Author information

1
Department of Biomedicine and Prevention, Universita' Tor Vergata, Rome, Italy.
2
Department of Hematology, Universita' Cattolica S. Cuore, Rome, Italy.
3
Department of Clinical Sciences and Community Health, Università degli studi di Milano, Italy.

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.

KEYWORDS:

NGS; clonal evolution; mutation; therapy-related neoplasms

PMID:
28076841
PMCID:
PMC5355323
DOI:
10.18632/oncotarget.14509
[Indexed for MEDLINE]
Free PMC Article

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