Single nucleotide polymorphism array lesions, TET2, DNMT3A, ASXL1 and CBL mutations are present in systemic mastocytosis.
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.
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
Fabiola
F
Traina
Valeria
V
Visconte
Anna M
AM
Jankowska
Hideki
H
Makishima
Christine L
CL
O'Keefe
Paul
P
Elson
Yingchun
Y
Han
Fred H
FH
Hsieh
Mikkael A
MA
Sekeres
Raghuveer Singh
RS
Mali
Matt
M
Kalaycio
Alan E
AE
Lichtin
Anjali S
AS
Advani
Hien K
HK
Duong
Edward
E
Copelan
Reuben
R
Kapur
Sara T
ST
Olalla Saad
Jaroslaw P
JP
Maciejewski
Ramon V
RV
Tiu
D000293:Adolescent; D000328:Adult; D000368:Aged; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D049308:Dioxygenases; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D007621:Karyotyping; D034721:Mastocytosis, Systemic / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*
C473949:ASXL1 protein, human; D017931:DNA Primers; D004268:DNA-Binding Proteins; C000717967:DNMT3A protein, human; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D049308:Dioxygenases; C541081:TET2 protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D050721:Proto-Oncogene Proteins c-cbl; C067419:CBL protein, human