Work

Clonal evolution in therapy-related neoplasms

Year: 2017

Type: article

Abstract: // Emiliano Fabiani 1, 2, * , Giulia Falconi 1, 2, * , Luana Fianchi 2 , Marianna Criscuolo 2 , Tiziana Ottone 1 , Laura Cicconi 1 , Stefan Hohaus 2 , Simona Sica 2 , Massimiliano Postorino 1 , Antonino Neri 3 , Marta Lionetti 3 , Giuseppe Leone 2 , Francesco Lo-Coco 1 , Maria Teresa Voso 1 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 * These authors have contributed equally to this work Correspondence to: Francesco Lo-Coco, email: [email protected] Keywords: therapy-related neoplasms, clonal evolution, NGS, mutation Received: April 13, 2016 Accepted: December 26, 2016 Published: January 05, 2017 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.

Source: Oncotarget

DOI: 10.18632/oncotarget.14509