Epigenetics Meets Genetics in Acute Myeloid Leukemia: Clinical Impact of a Novel Seven-Gene Score

Abstract

Purpose Molecular risk stratification of acute myeloid leukemia (AML) is largely based on genetic markers. However, epigenetic changes, including DNA methylation, deregulate gene expression and may also have prognostic impact. We evaluated the clinical relevance of integrating DNA methylation and genetic information in AML. Methods Next-generation sequencing analysis of methylated DNA identified differentially methylated regions (DMRs) associated with prognostic mutations in older (≥ 60 years) cytogenetically normal (CN) patients with AML (n = 134). Genes with promoter DMRs and expression levels significantly associated with outcome were used to compute a prognostic gene expression weighted summary score that was tested and validated in four independent patient sets (n = 355). Results In the training set, we identified seven genes (CD34, RHOC, SCRN1, F2RL1, FAM92A1, MIR155HG, and VWA8) with promoter DMRs and expression associated with overall survival (OS; P ≤ .001). Each gene had high DMR methylation and lower expression, which were associated with better outcome. A weighted summary expression score of the seven gene expression levels was computed. A low score was associated with a higher complete remission (CR) rate and longer disease-free survival and OS (P < .001 for all end points). This was validated in multivariable models and in two younger (< 60 years) and two older independent sets of patients with CN-AML. Considering the seven genes individually, the fewer the genes with high expression, the better the outcome. Younger and older patients with no genes or one gene with high expression had the best outcomes (CR rate, 94% and 87%, respectively; 3-year OS, 80% and 42%, respectively). Conclusion A seven-gene score encompassing epigenetic and genetic prognostic information identifies novel AML subsets that are meaningful for treatment guidance.

How I treat the older patient with acute myeloid leukemia

“…They use relative cutoff values (high vs low) rather than absolute values and therefore are more difficult to apply as a reference in clinical practice. 62 These accumulating genomic data mark the beginning of efforts to better understand and predict responsiveness and refractoriness to antileukemic drugs in individual patients.…”

Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics

“…Methylation analysis and survival analysis for AML patients was conducted for RIP3 using the methodology and data sets of Marcucci et al [53], with promoter methylation analysis defined as 1 kb upstream and 1 kb downstream of TSS.…”

Persistence of DNMT3A mutations at long‐term remission in adult patients with AML

“…As highlighted in recent comprehensive studies (Cancer Genome Atlas Research Network, 2013;Marcucci et al, 2014), epigenetic alterations and genetic alterations in epigenetic modifiers (Fathi & Abdel-Wahab, 2012) have been implicated in the pathogenesis of AML. Among the proteins that are important for epigenetic regulation of gene transcription that are targeted by somatic mutations in AML is DNA (cytosine-5-)-methyltransferase 3 alpha (DNMT3A), a de novo DNA methyltransferase that catalyses the addition of a methyl group to the cytosine of CpG dinucleotides.…”