Credit: NIGMS
A scoring system that combines genetic and epigenetic changes could help guide therapy for acute myeloid leukemia (AML), according to a study published in the Journal of Clinical Oncology.
The score is based on the presence of 7 mutated genes and DNA methylation.
For each of these genes, lower expression and higher DNA methylation were associated with better patient outcomes.
The investigators therefore believe this scoring system could guide treatment by identifying novel subsets of patients.
“To date, disease classification and prognostication for AML patients have been based largely on chromosomal and genetic markers,” said principal investigator Clara D. Bloomfield, MD, of The Ohio State University in Columbus.
“Epigenetic changes that affect gene expression have not been considered. Here, we show that epigenetic changes in previously recognized and prognostically important mutated genes can identify novel patient subgroups, which might better help guide therapy.”
Creating the score
Dr Bloomfield and her colleagues identified the 7-gene panel in 134 patients who were 60 and older, had cytogenetically normal AML (CN-AML), and had been treated on Cancer and Leukemia Group B/Alliance clinical trials.
The investigators used next-generation sequencing to analyze regions of methylated DNA associated with prognostically important genetic mutations. The 7 genes they identified are CD34, RHOC, SCRN1, F2RL1, FAM92A1, MIR155HG, and VWA8.
The team then developed a summary score based on the number of genes in the panel showing high expression.
And they applied the unweighted score to 126 of the aforementioned patients. Individuals with 1 or no highly expressed genes had a 96% complete remission (CR) rate, a 3-year disease-free survival (DFS) rate of 32%, and a 3-year overall survival (OS) rate of 39%.
Patients with 6 to 7 highly expressed genes, on the other hand, had a 25% CR rate, a 3-year DFS of 0%, and a 3-year OS of 4%.
Validating the system
The investigators also tested the score in 4 validation cohorts: older patients (age 60 and up) with primary AML (n=72), younger patients (59 and under) with primary AML (n=134), older patients with CN-AML (n=65), and younger patients with CN-AML (n=84).
“In both younger and older patients, those who had no highly expressed genes, or had one highly expressed gene, had the best outcomes,” said study author Guido Marcucci, MD, of The Ohio State University Comprehensive Cancer Center.
For the younger patients (with primary or CN-AML), individuals with 1 or no highly expressed genes had a 91% to 100% CR rate, a 3-year DFS of 60% to 65%, and a 3-year OS of 76% to 82%.
But younger patients with 6 to 7 highly expressed genes had a 53% to 71% CR rate, a 3-year DFS of 13% to 17%, and a 3-year OS of 7% to 24%.
For the older patients, individuals with 1 or no highly expressed genes had a 69% to 89% CR rate, a 3-year DFS of 42% (CN-AML only), and a 3-year OS of 44% to 46%.
Older patients with 6 to 7 highly expressed genes had a 50% CR rate (both types of AML), a 3-year DFS of 0% (CN-AML only), and a 3-year OS of 10% to 12%. DFS data were not evaluable for the older patients with primary AML due to the small sample size.
“Overall, our findings suggest that the unweighted summary score is a better model compared with all other prognostic markers and previously reported gene-expression profiles,” Dr Bloomfield concluded.
