2009.03.05 – Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates

http://www.nature.com/leu/journal/v23/n5/abs/leu200937a.html

Original Article
Leukemia (2009) 23, 900–904; doi:10.1038/leu.2009.37; published online 5 March 2009

Chronic Myeloproliferative Neoplasias

Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates

A Tefferi1, R L Levine2,3, K-H Lim1,4, O Abdel-Wahab2,3, T L Lasho1, J Patel2, C M Finke1, A Mullally5, C-Y Li1, A Pardanani1 and D G Gilliland5,6

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 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.

1Divisions of Hematology and Hematopathology, Departments of Medicine and Laboratory Medicine, Mayo Clinic, Rochester, MN, USA
2Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
3Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
4Division of Hematology-Oncology, Mackay Memorial Hospital and Mackay Medicine, Nursing and Management College, Taipei, Taiwan
5Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
6Howard Hughes Medical Institute, Boston, MA, USA
Correspondence: Professor A Tefferi, Divisions of Hematology and Hematopathology, Departments of Medicine and Laboratory Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. E-mail: tefferi.ayalew@mayo.edu
Received 23 January 2009; Accepted 29 January 2009; Published online 5 March 2009.