title: Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates.
abstract: 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.
authors.affiliation: Divisions of Hematology and Hematopathology, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA. tefferi.ayalew@mayo.edu
authors.forename: A
authors.initials: A
authors.lastname: Tefferi
authors.forename: R L
authors.initials: RL
authors.lastname: Levine
authors.forename: K-H
authors.initials: KH
authors.lastname: Lim
authors.forename: O
authors.initials: O
authors.lastname: Abdel-Wahab
authors.forename: T L
authors.initials: TL
authors.lastname: Lasho
authors.forename: J
authors.initials: J
authors.lastname: Patel
authors.forename: C M
authors.initials: CM
authors.lastname: Finke
authors.forename: A
authors.initials: A
authors.lastname: Mullally
authors.forename: C-Y
authors.initials: CY
authors.lastname: Li
authors.forename: A
authors.initials: A
authors.lastname: Pardanani
authors.forename: D G
authors.initials: DG
authors.lastname: Gilliland
mesh_terms: 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*
chemical_list: 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