Oncotarget

Research Papers:

Clonal evolution in therapy-related neoplasms

Emiliano Fabiani, Giulia Falconi, Luana Fianchi, Marianna Criscuolo, Tiziana Ottone, Laura Cicconi, Stefan Hohaus, Simona Sica, Massimiliano Postorino, Antonino Neri, Marta Lionetti, Giuseppe Leone, Francesco Lo-Coco _ and Maria Teresa Voso

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Oncotarget. 2017; 8:12031-12040. https://doi.org/10.18632/oncotarget.14509

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Abstract

Emiliano Fabiani1,2,*, Giulia Falconi1,2,*, Luana Fianchi2, Marianna Criscuolo2, Tiziana Ottone1, Laura Cicconi1, Stefan Hohaus2, Simona Sica2, Massimiliano Postorino1, Antonino Neri3, Marta Lionetti3, Giuseppe Leone2, Francesco Lo-Coco1, Maria Teresa Voso1

1Department of Biomedicine and Prevention, Universita’ Tor Vergata, Rome, Italy

2Department of Hematology, Universita’ Cattolica S. Cuore, Rome, Italy

3Department 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.


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