Clonal evolution in therapy-related neoplasms

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

Research output: Contribution to journalArticle

11 Citations (Scopus)

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 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 (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.
Original languageEnglish
Pages (from-to)12031-12040
Number of pages10
JournalOncotarget
Volume8
DOIs
Publication statusPublished - 2017

Keywords

  • Clonal evolution
  • Mutation
  • NGS
  • Oncology
  • Therapy-related neoplasms

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