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DNMT3A mutation predicts adverse outcome in adult T-ALL
the spectrum of alterations across this gene in T-ALL. Diagnostic DNA was available for 198 patients treated during the GRAALL-2003 and -2005 studies. A partial analysis of a subgroup of this cohort has been reported previously.24 We detected 21 DNMT3A mutations in 18 patients (9.1%). Most alterations occurred in regions cod- ing for defined protein functional domains, including six mutations at the R882 hotspot1 (Figure 1A). Further details of patient-specific alterations are shown in Online Supplementary Table S3. Of note, the vast majority of detected mutations are predicted to be significantly dam- aging to protein function.
In keeping with previous reports of DNMT3A-mutated
A
T-ALL which cited high rates of either compound het- erozygosity or homozygosity,9,11 a significant proportion of cases (8/18) had either two separate alterations, or high variant allele frequencies that were suggestive of either homozygous mutation, concomitant deletion of the wild- type (WT) allele or copy-neutral loss of heterozygosity. Comparative genomic hybridization analyses were avail- able for 85 of the cases in this study, including 6/18 patients with DNMT3A mutations. We detected only two deletions of the DNMT3A locus, which in each case were associated with concomitant DNMT3A mutation and ele- vated variant allele frequencies (cases 11 and 12 in Online Supplementary Table S3).
B
Figure 1. DNMT3A mutations in T-cell acute lymphoblastic leukemia. (A) Schematic representation of the 21 mutations detected in this study. Further patient-spe- cific details are provided in Online Supplementary Table S3. (B) Comparison of the mutational genotypes of DNMT3A altered (n=18) and DNMT3A wild-type (n=180) T-cell acute lymphoblastic leukemia. Percentage frequencies in each group are depicted. Functional categories are listed in bold.
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