Jason Mendler, MD, PhD, and William Blum, MD
It has been nearly impossible to attend one of this year’s myelodysplastic syndrome (MDS) oral sessions without hearing about gene mutations affecting DNA methylation. Approximately one-third of all the MDS oral presentations deal with some aspect of identifying these mutations and understanding their functional, prognostic, and therapeutic significance. If one also considers the other talks addressing novel therapeutic approaches with azacitidine, a demethylating agent, one might wonder if the disease should be renamed methylation syndrome. What is this methylation rage all about?
MDS genomes are characterized by global DNA hypomethylation with concomitant hypermethylation of gene-promoter regions relative to normal controls. This causes transcriptional repression of certain genes, which is thought to promote MDS and eventual leukemogenesis. Currently, the underlying mechanism of altered-DNA methylation in MDS genomes is unclear. The discovery in MDS (and acute myeloid leukemia) of mutations in genes involved in DNA methylation is now providing a link between genetics and epigenetics in these disorders. These mutations also have prognostic significance in patients.
Several groups analyzed MDS patient samples to better characterize the prevalence and prognostic significance of DNA-methylation-altering mutations. Austin Kulasekararaj reported on the prevalence and prognostic significance of ASXL1 and EZH2 mutations in 63 MDS patients treated with azacitidine (abstract #125). They found that at least one of these mutations was present in 40 percent of patients and that these patients had a better prognosis relative to unmutated counterparts. Dr. Raphael Itzykson discussed TET2 mutational status in 103 pre-treatment MDS and AML post-MDS patients treated with azacitidine in six centers (abstract #439). Their group found TET2 mutations in 17 percent of these patients and that these patients had a better outcome with azacitidine therapy. Dr. Rafael Bejar conducted a broad survey for gene mutations in a cohort of 438 clinically annotated MDS patient samples and found TET2 mutations in 18 percent and ASXL1 mutations in 14 percent (abstract #300). In this study, ASXL1 mutations (in addition to RUNX1 and TP53) portended a worse prognosis. In a broad molecular screen of 63 patients with CMML, Anna Jankowska, MSc, found mutations in TET2 (48%), ASXL1 (24%), EZH2 (8%), and UTX (6%) (abstract #611). There was a trend toward better outcomes in TET2 mutants compared to wild type in the good cytogenetic risk group but worse outcomes in TET2 mutants in the intermediate cytogenetic risk group.
Dr. Matthew Walter and colleagues at Washington University described DNA methyltransferase 3A (DNMT3A) mutations for the first time in MDS (abstract #299). They looked for this mutation in MDS, given its presence in AML and association with worse outcome. They investigated 150 MDS patients for the presence of DNMT3A mutations. This gene was mutated in 12 out of 150 patients tested (8 percent) and seemed to portend a worse prognosis, although the small sample size precluded proper outcome analysis.
In case you would like to learn more about MDS, there is one more oral session today at 7:30 a.m. in Hall F3/F4 of the Orange County Convention Center. Don’t miss out on the rage!
Drs. Mendler and Blum indicated no relevant conflicts of interest.