title: Clonal evolution in therapy-related neoplasms.
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.
authors.affiliation: Department of Biomedicine and Prevention, Universita' Tor Vergata, Rome, Italy.|Department of Hematology, Universita' Cattolica S. Cuore, Rome, Italy.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Fabiani
authors.affiliation: Department of Biomedicine and Prevention, Universita' Tor Vergata, Rome, Italy.|Department of Hematology, Universita' Cattolica S. Cuore, Rome, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Falconi
authors.affiliation: Department of Hematology, Universita' Cattolica S. Cuore, Rome, Italy.
authors.forename: Luana
authors.initials: L
authors.lastname: Fianchi
authors.affiliation: Department of Hematology, Universita' Cattolica S. Cuore, Rome, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Criscuolo
authors.affiliation: Department of Biomedicine and Prevention, Universita' Tor Vergata, Rome, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Ottone
authors.affiliation: Department of Biomedicine and Prevention, Universita' Tor Vergata, Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Cicconi
authors.affiliation: Department of Hematology, Universita' Cattolica S. Cuore, Rome, Italy.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hohaus
authors.affiliation: Department of Hematology, Universita' Cattolica S. Cuore, Rome, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Sica
authors.affiliation: Department of Biomedicine and Prevention, Universita' Tor Vergata, Rome, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Postorino
authors.affiliation: Department of Clinical Sciences and Community Health, Università degli studi di Milano, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Neri
authors.affiliation: Department of Clinical Sciences and Community Health, Università degli studi di Milano, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Lionetti
authors.affiliation: Department of Hematology, Universita' Cattolica S. Cuore, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Leone
authors.affiliation: Department of Biomedicine and Prevention, Universita' Tor Vergata, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Lo-Coco
authors.affiliation: Department of Biomedicine and Prevention, Universita' Tor Vergata, Rome, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Voso
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D060965:Clonal Evolution; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016609:Neoplasms, Second Primary / Q000235:genetics* / Q000473:pathology
keywords: NGS; clonal evolution; mutation; therapy-related neoplasms