Single Nucleotide Polymorphism Array Lesions, TET2, DNMT3A, ASXL1 and CBL Mutations Are Present in Systemic Mastocytosis

Fabı́ola Traina(Cleveland Clinic), Valeria Visconte(Cleveland Clinic), A. Jankowska(Cleveland Clinic), Hideki Makishima(Cleveland Clinic), Christine L. O’Keefe(Cleveland Clinic), Paul Elson(Cleveland Clinic), Yingchun Han(Cleveland Clinic Lerner College of Medicine), Fred H. Hsieh(Cleveland Clinic Lerner College of Medicine), Mikkael A. Sekeres(Cleveland Clinic), Raghuveer Singh Mali(Indiana University – Purdue University Indianapolis), Matt Kalaycio(Cleveland Clinic), Alan Lichtin(Cleveland Clinic), Anjali S. Advani(Cleveland Clinic), Hien K. Duong(Cleveland Clinic), Edward A. Copelan(Cleveland Clinic), Reuben Kapur(Indiana University – Purdue University Indianapolis), Sara Teresinha Olalla Saad(Universidade Estadual de Campinas (UNICAMP)), Jaroslaw P. Maciejewski(Cleveland Clinic), Ramón V. Tiu(Cleveland Clinic)
PLoS ONE
August 15, 2012
10.1371/journal.pone.0043090
Cited by 116Open Access
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Abstract

We hypothesized that analysis of single nucleotide polymorphism arrays (SNP-A) and new molecular defects may provide new insight in the pathogenesis of systemic mastocytosis (SM). SNP-A karyotyping was applied to identify recurrent areas of loss of heterozygosity and bidirectional sequencing was performed to evaluate the mutational status of TET2, DNMT3A, ASXL1, EZH2, IDH1/IDH2 and the CBL gene family. Overall survival (OS) was analyzed using the Kaplan-Meier method. We studied a total of 26 patients with SM. In 67% of SM patients, SNP-A karyotyping showed new chromosomal abnormalities including uniparental disomy of 4q and 2p spanning TET2/KIT and DNMT3A. Mutations in TET2, DNMT3A, ASXL1 and CBL were found in 23%, 12%, 12%, and 4% of SM patients, respectively. No mutations were observed in EZH2 and IDH1/IDH2. Significant differences in OS were observed for SM mutated patients grouped based on the presence of combined TET2/DNMT3A/ASXL1 mutations independent of KIT (P = 0.04) and sole TET2 mutations (P<0.001). In conclusion, TET2, DNMT3A and ASXL1 mutations are also present in mastocytosis and these mutations may affect prognosis, as demonstrated by worse OS in mutated patients.

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