Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates.
TET2 (TET oncogene family member 2) is a candidate tumor suppressor gene located at chromosome 4q24, and was recently reported to be mutated in approximately 14% of patients with JAK2V617F-positive myeloproliferative neoplasms. We used high-throughput DNA sequence analysis to screen for TET2 mutations in bone marrow-derived DNA from 48 patients with systemic mastocytosis (SM), including 42 who met the 2008 WHO (World Health Organization) diagnostic criteria for SM and 6 with FIP1L1-PDGFRA. Twelve (29%) SM, but no FIP1L1-PDGFRA patients, had TET2 mutations. A total of 17 mutations (13 frameshift, 2 nonsense and 2 missense) were documented in 2 (15%) of 13 indolent SM patients, 2 (40%) of 5 aggressive SM, and 8 (35%) of 23 SM associated with a clonal non-mast cell-lineage hematopoietic disease (P=0.52). KITD816V was detected by PCR sequencing in 50 or 20% of patients with or without TET2 mutation (P=0.05), respectively. Multivariable analysis showed a significant association between the presence of TET2 mutation and monocytosis (P=0.0003) or female sex (P=0.05). The association with monocytosis was also observed in non-indolent SM (n=29), in which the presence of mutant TET2 did not affect survival (P=0.98). We conclude that TET2 mutations are frequent in SM, segregate with KITD816V and influence phenotype without necessarily altering prognosis.
Tefferi
A
A
Divisions of Hematology and Hematopathology, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA. tefferi.ayalew@mayo.edu
Levine
R L
RL
Lim
K-H
KH
Abdel-Wahab
O
O
Lasho
T L
TL
Patel
J
J
Finke
C M
CM
Mullally
A
A
Li
C-Y
CY
Pardanani
A
A
Gilliland
D G
DG
D000368:Aged; D000369:Aged, 80 and over; D004268:DNA-Binding Proteins / Q000235:genetics*; D049308:Dioxygenases; D005260:Female; D006801:Humans; D008297:Male; D034721:Mastocytosis, Systemic / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D015996:Survival Rate; D039221:mRNA Cleavage and Polyadenylation Factors / Q000235:genetics*
D004268:DNA-Binding Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D039221:mRNA Cleavage and Polyadenylation Factors; D049308:Dioxygenases; C541081:TET2 protein, human; C479819:FIP1L1-PDGFRA fusion protein, human; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha