title: Comprehensive mutational profiling in advanced systemic mastocytosis.
abstract: To explore mechanisms contributing to the clinical heterogeneity of systemic mastocytosis (SM) and to suboptimal responses to diverse therapies, we analyzed 39 KIT D816V mutated patients with indolent SM (n = 10), smoldering SM (n = 2), SM with associated clonal hematologic nonmast cell lineage disorder (SM-AHNMD, n = 5), and aggressive SM (n = 15) or mast cell leukemia (n = 7) with (n = 18) or without (n = 4) AHNMD for additional molecular aberrations. We applied next-generation sequencing to investigate ASXL1, CBL, IDH1/2, JAK2, KRAS, MLL-PTD, NPM1, NRAS, TP53, SRSF2, SF3B1, SETBP1, U2AF1 at mutational hotspot regions, and analyzed complete coding regions of EZH2, ETV6, RUNX1, and TET2. We identified additional molecular aberrations in 24/27 (89%) patients with advanced SM (SM-AHNMD, 5/5; aggressive SM/mast cell leukemia, 19/22) whereas only 3/12 (25%) indolent SM/smoldering SM patients carried one additional mutation each (U2AF1, SETBP1, CBL) (P < .001). Most frequently affected genes were TET2, SRSF2, ASXL1, CBL, and RUNX1. In advanced SM, 21/27 patients (78%) carried ≥3 mutations, and 11/27 patients (41%) exhibited ≥5 mutations. Overall survival was significantly shorter in patients with additional aberrations as compared to those with KIT D816V only (P = .019). We conclude that biology and prognosis in SM are related to the pattern of mutated genes that are acquired during disease evolution.
authors: III. Medizinische Klinik, Hämatologie und Onkologie, Universitätsmedizin Mannheim, Mannheim, Germany;
authors: Juliana
authors: J
authors: Schwaab
authors: Susanne
authors: S
authors: Schnittger
authors: Karl
authors: K
authors: Sotlar
authors: Christoph
authors: C
authors: Walz
authors: Alice
authors: A
authors: Fabarius
authors: Markus
authors: M
authors: Pfirrmann
authors: Alexander
authors: A
authors: Kohlmann
authors: Vera
authors: V
authors: Grossmann
authors: Manja
authors: M
authors: Meggendorfer
authors: Hans-Peter
authors: HP
authors: Horny
authors: Peter
authors: P
authors: Valent
authors: Mohamad
authors: M
authors: Jawhar
authors: Martina
authors: M
authors: Teichmann
authors: Georgia
authors: G
authors: Metzgeroth
authors: Philipp
authors: P
authors: Erben
authors: Thomas
authors: T
authors: Ernst
authors: Andreas
authors: A
authors: Hochhaus
authors: Torsten
authors: T
authors: Haferlach
authors: Wolf-Karsten
authors: WK
authors: Hofmann
authors: Nicholas C P
authors: NC
authors: Cross
authors: Andreas
authors: A
authors: Reiter
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004252:DNA Mutational Analysis; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D034721:Mastocytosis, Systemic / Q000235:genetics*; D008875:Middle Aged; D000090243:Nucleophosmin; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics
chemical_list: C000716967:NPM1 protein, human; D000090243:Nucleophosmin; D019009:Proto-Oncogene Proteins c-kit