Next-generation sequencing of the TET2 gene in 355 MDS and CMML patients reveals low-abundance mutant clones with early origins, but indicates no definite prognostic value

Abstract

Mutations in the TET2 gene are frequent in myeloid disease, although their biologic and prognostic significance remains unclear. We analyzed 355 patients with myelodysplastic syndromes using "next-generation" sequencing for TET2 aberrations, 91 of whom were also subjected to single-nucleotide polymorphism 6.0 array karyotyping. Seventy-one TET2 mutations, with a relative mutation abundance (RMA) > 10%, were identified in 39 of 320 (12%) myelodysplastic syndrome and 16 of 35 (46%) chroni myelomonocytic leukemia patients (P < .001).Interestingly, 4 patients had multiple mutations likely to exist as independent clones or on alternate alleles, suggestive of clonal evolution. "Deeper" sequencing of 96 patient samples identified 4 additional mutations (RMA, 3%-6.3%). Importantly, TET2 mutant clones were also found in T cells, in addition to CD34 ؉ and total bone marrow cells (23.5%, 38.5%, and 43% RMA, respectively). Only 20% of the TET2-mutated patients showed loss of heterozygosity at the TET2 locus. There was no difference in the frequency of genome-wide aberrations, TET2 expression, or the JAK2V617F 46/1 haplotype between TET2-mutated and nonmutated patients. There was no significant prognostic association between TET2 mutations and World Health Organization subtypes, International Prognostic Scoring System score, cytogenetic status, or transformation to acute myeloid leukemia. On multivariate analysis, age (> 50 years) was associated with a higher incidence of TET2 mutation (P ‫؍‬ .02).

Development of monocytosis in patients with primary myelofibrosis indicates an accelerated phase of the disease

“…28 TET2 mutations are the most common genetic abnormality found in chronic myelomonocytic leukemia, being present in around 40% cases. 29,30 Although TET2 mutations can represent early molecular events in myeloproliferative neoplasms, in a recent study of JAK2 mutation-positive myeloproliferative neoplasms based on colony assays, genotyping for TET2 and JAK2 mutations, it was demonstrated that TET2 can be a late event in the progression of myeloproliferative neoplasms and may represent an acquired abnormality in a separate (JAK2 mutation-negative) clone. 31 It is intriguing to speculate that the acquisition of KRAS, TET2 or other mutagenic events could have played a role in the phenotypic shift observed in our cases.…”

Comprehensive array CGH of normal karyotype myelodysplastic syndromes reveals hidden recurrent and individual genomic copy number alterations with prognostic relevance

“…Two patients had deletions in 4q removing the entire TET2 gene. Although TET2 was identified as the most frequently mutated gene in MDS, [18][19][20] its role in disease remains controversial; two reports describe no impact of TET2 mutations on survival in MDS/MPD (myeloproliferative disease), 18,21 another describes an association with decreased overall survival in AML 13 and, most recently, TET2 mutations were reported to be an independent favorable prognostic factor in MDS. 22 Two patients had submicroscopic deletions in 5q; one was only 1.35 Mb in 5q31.2, affecting the more proximal AML/MDS region.…”

The Interlaboratory RObustness of Next-generation sequencing (IRON) study: a deep sequencing investigation of TET2, CBL and KRAS mutations by an international consortium involving 10 laboratories

“…1,2 It has become apparent that NGS platforms will have practical applications in clinical diagnostics and applications, such as detection of EGFR mutations in lung adenocarcinoma, 3 characterizing RAS and methylation pathway alterations in myeloproliferative diseases and myeloid leukemias, [4][5][6][7] or high-resolution, high-throughput human leukocyte antigen genotyping have been developed. 8,9 Thus far, limited data are available on the technical performance of amplicon deep sequencing in a clinical diagnostic setting.…”