TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients

Abstract

Only a minority of myelodysplastic syndrome (MDS) patients respond to hypomethylating agents (HMAs), but strong predictors of response are unknown. We sequenced 40 recurrently mutated myeloid malignancy genes in tumor DNA from 213 MDS patients collected before treatment with azacitidine (AZA) or decitabine (DEC). Mutations were examined for association with response and overall survival. The overall response rate of 47% was not different between agents. Clonal TET2 mutations predicted response (odds ratio [OR] 1.99, P = .036) when subclones unlikely to be detected by Sanger sequencing (allele fraction <10%) were treated as wild-type (WT). Response rates were highest in the subset of TET2 mutant patients without clonal ASXL1 mutations (OR 3.65, P = .009). Mutations of TP53 (hazard ratio [HR] 2.01, P = .002) and PTPN11 (HR 3.26, P = .006) were associated with shorter overall survival but not drug response. Murine-competitive bone marrow transplantation followed by treatment with AZA demonstrated that Tet2-null cells have an engraftment advantage over Tet2-WT cells. AZA significantly decreased this advantage for Tet2-null cells (P = .002) but not Tet2-WT cells (P = .212). Overall, Tet2 loss appears to sensitize cells to treatment with AZA in vivo, and TET2 mutations can identify patients more likely to respond to HMAs.

© 2014 by The American Society of Hematology.

Figures

Figure 1

Spectrum of mutations in 213 patients in select MDS-associated genes. Each column represents an individual patient sample, and each colored cell represents a mutation of the gene or gene group listed to left of that row. The number of mutations for each row is indicated in the column to the right. Darker bars in the ASXL1 row indicate patients with a p.G642fs mutation. TK Pathway = NRAS, KRAS, CBL, CBLB, JAK2, PTPN11, BRAF, MPL, and KIT.

Figure 2

Variant allele frequencies in selected genes. (A) Quantitative measure of variant-containing reads estimates the abundance of these mutations (uncorrected for allele copy number). Mutations of TET2 (green), TP53 (orange), and splicing factor genes (red) are often present in the dominant clone, whereas mutations of tyrosine kinase–signaling genes (blue) are often present in smaller clones. Mutations of ASXL1 (yellow) are more widely distributed. (B) Analysis of samples with both TET2 and ASXL1 mutations indicate that ASXL1 mutations are most often codominant with, or smaller than, TET2-mutant clones.

Figure 3

Peripheral blood chimerism. Shown over time after competitive bone marrow transplantation with cells from 45.2 Tet2-null mice (A) and 45.2 Tet2-WT mice (B). Gray bars indicate periods of treatment with AZA or vehicle. Tet2-null cells show increased chimerism compared with Tet2-WT cells. Treatment with AZA significantly decreases chimerism in the Tet2-null recipient mice only. *P < .05, **P < .01.

Figure 4

Kaplan-Meier curves for overall survival in the 146 out of 213 study patients with survival data. (A) Survival of patients with and without TET2 mutations. (B) Survival of patients with and without TP53 mutations. (C) Survival of patients with and without PTPN11 mutations. (D) Survival of complex karyotype patients with and without TP53 mutations vs patients without complex karyotypes.