In a broad survey of mutations in 439 primary DNA samples from patients with myelodysplastic syndromes, we identified point mutations in 18 genes, including 2 (ETV6 and GNAS) that have not previously been reported to harbor mutations in such patients. We found that several of these genetic lesions correlate strongly with features of the clinical phenotype, including specific cytopenias, blast percentage, cytogenetic abnormalities, and overall survival. In a multivariable analysis that included clinical features and other mutations, mutations in five genes — TP53, EZH2, ETV6, RUNX1, and ASXL1 — were independently associated with decreased overall survival. Mutations in one or more of these genes were present in 137 of the 439 patients (31.2%). These findings indicate that mutations in specific genes help explain the clinical heterogeneity of myelodysplastic syndromes and that the identification of these abnormalities would improve the prediction of prognosis in patients with myelodysplastic syndromes.
By analyzing copy-number alterations with the use of SNP arrays and oncogene mutations, by means of high-throughput genotyping, we identified new mutations in ETV6
. Both translocations and mutations of ETV6
have been identified in acute myeloid leukemia, and translocations have been described in rare cases of myelodysplastic syndromes, but ETV6
mutations have not previously been reported in myelodysplastic syndromes.27,28
We also identified three samples with activating mutations of amino acid R201 in GNAS
, the gene encoding the GSα
subunit of the heterotrimeric GS
-protein complex. Identical somatic activating mutations of GNAS
have been identified in several types of solid tumors but not in hematologic cancers.29–32
In general, our data support the idea that activating mutations of oncogenes are relatively infrequent in myelodysplastic syndromes. Our survey of more than 900 mutations in 111 cancer-associated genes identified only 6 mutated oncogenes, which were present in less than 10% of samples.
Prognostically significant somatic mutations occurred in patients in all risk groups. Most patients with EZH2 or ASXL1 mutations had low or intermediate-1 risk according to the IPSS (86% and 73%, respectively). The presence (vs. the absence) of EZH2 mutations was strongly associated with decreased overall survival in the stepwise, multivariable model that considered age, sex, IPSS risk group, and the presence of other mutations (hazard ratio for death, 2.13 [95% CI, 1.36 to 3.33]). The presence (vs. the absence) of mutations of ASXL1 carried a more modest hazard ratio for death (1.38 [95% CI, 1.00 to 1.89]), but ASXL1, as the second most commonly mutated gene identified in this study, contributed additional risk to the greatest number of patients. Therefore, lower-risk patients with myelodysplastic syndromes who have EZH2 and ASXL1 mutations may require more aggressive treatment than would be predicted by the IPSS.
In contrast, TP53
mutations were observed mainly in patients with intermediate-2 or high risk according to the IPSS (79%) and were strongly associated with thrombocytopenia, an elevated blast proportion, and a complex karyotype. Even though these measures are integrated into the IPSS, TP53
mutations remained strongly associated with shorter overall survival after adjustment for IPSS risk group (P<0.001), indicating that these mutations adversely affect survival through other means (Fig. 5 in the Supplementary Appendix
). Furthermore, patients with mutant TP53
and a complex karyotype had a paucity of mutations in other genes, suggesting that this group could be considered to have a distinct molecular subclass of myelodysplastic syndromes with a unique pathogenic mechanism.
mutations were the most prevalent genetic abnormality identified in our sample set. These mutations were not strongly associated with clinical features such as cytopenias or blast proportion, findings that are consistent with the observation that TET2
mutations occur in diverse myeloid cancers, including myeloproliferative neoplasms, that are not characterized by defects in hematopoietic differentiation. More than one quarter (26%) of the samples with at least one TET2
mutation had two distinct TET2
mutations, suggesting that biallelic loss of wild-type TET2
contributes to the pathogenesis of myelodysplastic syndromes in some cases. In contrast to previously reported findings in smaller sample sets, neither monoallelic nor biallelic mutations were associated with IPSS risk group or overall survival (Fig. 6 in the Supplementary Appendix
Furthermore, analysis of the mutant-allele burden in samples with mutations of TET2
and other genes showed that TET2
mutations are not always present at the greatest frequency, which would be expected if they were exclusively involved in early pathogenic events (Fig. 7 in the Supplementary Appendix
mutations were not exclusive of abnormalities in other epigenetic regulators such as the chromatin-modifying genes ASXL1
Mutations in ASXL1
had associations with clinical phenotypes, including overall survival, that differed from those of TET2
mutations, suggesting that these genes drive distinct and additive aspects of cellular transformation to myelodysplastic syndromes.
Each of the prognostically significant mutations most likely alters the biologic characteristics and phenotype of myelodysplastic syndromes in unique ways, as is the case for cytogenetic abnormalities, with complex interactions among combinations of genetic and epigenetic lesions. Nevertheless, a simplified prognostic scoring scheme has great clinical value. One approach to improving the IPSS would be to include one additional variable: the presence or absence of a mutation in any of the five genes with independent prognostic significance. The presence of such a mutation would reclassify patients into the next highest IPSS risk group.
As our study shows, somatic mutations in several genes are associated with distinct effects on cytopenias, blast proportion, the likelihood of co-occurrence with other molecular lesions, and overall survival. It will soon be possible for clinicians to detect a broad range of point mutations in peripheral blood with the use of sensitive genotyping methods, which will not only improve prognostication in myelodysplastic syndromes but also facilitate the diagnosis of these disorders, the evaluation of disease progression, and the monitoring of response to treatment. The integration of mutation assessment in diagnostic classification and prognostic scoring systems has the potential to parse diverse myelodysplastic syndromes into a set of discrete diseases with predictable clinical phenotypes, prognosis, and responses to therapy.