title: Additional mutations in SRSF2, ASXL1 and/or RUNX1 identify a high-risk group of patients with KIT D816V(+) advanced systemic mastocytosis.
abstract: Most patients with KIT D816V(+) advanced systemic mastocytosis (SM) are characterized by somatic mutations in additional genes. We sought to clarify the prognostic impact of such mutations. Genotype and clinical characteristics of 70 multi-mutated KIT D816V(+) advanced SM patients were included in univariate and multivariate analyses. The most frequently identified mutated genes were TET2 (n=33 of 70 patients), SRSF2 (n=30), ASXL1 (n=20), RUNX1 (n=16) and JAK2 (n=11). In univariate analysis, overall survival (OS) was adversely influenced by mutations in SRSF2 (P<0.0001), ASXL1 (P=0.002) and RUNX1 (P=0.03), but was not influenced by mutations in TET2 or JAK2. In multivariate analysis, SRSF2 and ASXL1 remained the most predictive adverse indicators concerning OS. Furthermore, we found that inferior OS and adverse clinical characteristics were significantly influenced by the number of mutated genes in the SRSF2/ASXL1/RUNX1 (S/A/R) panel (P<0.0001). In conclusion, the presence and number of mutated genes within the S/A/R panel are adversely associated with advanced disease and poor survival in KIT D816V(+) SM. On the basis of these findings, inclusion of molecular markers should be considered in upcoming prognostic scoring systems for patients with SM.
authors.affiliation: Department of Hematology and Oncology, University Medical Centre Mannheim, Mannheim, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Jawhar
authors.affiliation: Department of Hematology and Oncology, University Medical Centre Mannheim, Mannheim, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Schwaab
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schnittger
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Meggendorfer
authors.affiliation: Institute for Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians University, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Pfirrmann
authors.affiliation: Institute of Pathology, Ludwig-Maximilians University, Munich, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Sotlar
authors.affiliation: Institute of Pathology, Ludwig-Maximilians University, Munich, Germany.
authors.forename: H-P
authors.initials: HP
authors.lastname: Horny
authors.affiliation: Department of Hematology and Oncology, University Medical Centre Mannheim, Mannheim, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Metzgeroth
authors.affiliation: Department of Hematology and Oncology, University Medical Centre Mannheim, Mannheim, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Kluger
authors.affiliation: Department of Hematology and Oncology, University Medical Centre Mannheim, Mannheim, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Naumann
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Haferlach
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Haferlach
authors.affiliation: Division of Hematology and Ludwig Boltzmann Cluster Oncology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria.
authors.forename: P
authors.initials: P
authors.lastname: Valent
authors.affiliation: Department of Hematology and Oncology, University Medical Centre Mannheim, Mannheim, Germany.
authors.forename: W-K
authors.initials: WK
authors.lastname: Hofmann
authors.affiliation: Department of Hematology and Oncology, University Medical Centre Mannheim, Mannheim, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Fabarius
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury, UK.|Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: N C P
authors.initials: NC
authors.lastname: Cross
authors.affiliation: Department of Hematology and Oncology, University Medical Centre Mannheim, Mannheim, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Reiter
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D006801:Humans; D034721:Mastocytosis, Systemic / Q000097:blood / Q000235:genetics* / Q000401:mortality; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D012261:Ribonucleoproteins / Q000235:genetics*; D012306:Risk; D000068103:Serine-Arginine Splicing Factors
chemical_list: C473949:ASXL1 protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D009687:Nuclear Proteins; C493728:RUNX1 protein, human; D012097:Repressor Proteins; D012261:Ribonucleoproteins; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors; D019009:Proto-Oncogene Proteins c-kit