Whole-Genome Sequencing May Improve Prognosis Accuracy for AML/MDS Versus Traditional Cytogenetics

According to a single-institution study of patients with a known or suspected diagnosis of AML or MDS, whole-genome sequencing may provide better predictive ability of patients’ risk status than traditional methods.

When whole-genome sequencing was studied as a sequencing approach for risk-stratification in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), greater diagnostic yield and more efficient stratification based on risk categories were noted in comparison with conventional cytogenetics.1

Whole-genome sequencing was able to detect 100% of the clinically significant abnormalities that had appeared on cytogenetic analysis and fluorescence in situ hybridization (FISH). In addition, new genetic information was gathered in one-quarter (24.8%) of patients, half of whom (16.2%) were reassigned to a new risk group.

“Choosing the appropriate therapy for patients often depends on identifying a range of different types of genetic changes in a patient’s tumor cells,” corresponding author David H. Spencer, MD, PhD, assistant professor of medicine and medical director of the clinical sequencing facility at the McDonnell Genome Institute, said in a news release.2 “Our study suggests whole-genome sequencing is a reliable and practical approach for detecting all of the changes that are important for assessing the risk of relapse for AML and MDS, using a single test. This approach can be performed when conventional testing methods are unsuccessful and also could be applied to other cancers, including solid tumors. This means that patients with other cancer types eventually could benefit from rapid clinical genome sequencing.”

Forty recurrent translocations and 91 copy-number alterations were detected by both whole-genome sequencing and cytogenetic analysis. New clinically reportable genomic events were noted in 17.0% or 40 out of 235 patients.

Investigators also noted that results from whole-genome sequencing were able to accurately stratify patients into risk groups that correlated with their clinical outcomes and offers the ability to assess and stratify patients with inconclusive cytogenetic analyses.

Survival in patients who had risk predicted by whole-exome sequencing supported its use, given a median overall survival of 20.5 (95% CI, 5.6-38.8) months for those with an intermediate- or favorable-risk score versus 3.3 months (95% CI, 1.7-18.9) in those with and adverse-risk score (HR, 0.29; 95% CI, 0.09-0.94; P = .03). These outcomes compared favorably to those in patients assigned to a risk group by traditional cytogenetics.

“For these [patients], conventional chromosome analysis is a critical part of the standard diagnostic work-up,” Spencer said. “We know from research studies that whole-genome sequencing can detect these types of chromosomal abnormalities, so that part of our study is not terribly surprising. What we showed is that genome sequencing has reached a point that it is now practical, fast, economical, clinically feasible and accessible for the routine testing of patients.”

In real-world practice, the investigators noted that diagnostic yield of this approach will rely on a number of factors, such as laboratory-specific karyotyping practices and the use of FISH or other ancillary testing. As such, certain diagnostic assays, such as polymerase chain reaction tests for specific rearrangements and mutations, may be warranted for rapid decision making.

Although this proof-of-concept study demonstrates the feasibility of using whole-genome sequencing for risk stratification, larger studies would be necessary to establish this claim. Additionally, a barrier to its use across many settings would be the costs associated with its implementation.

“Implementing whole-genome sequencing for clinical testing can provide a unified, stable, and extensible platform that minimizes laboratory-specific bias and that can be standardized throughout the world,” the study authors wrote in their conclusion. “Such an approach would simplify genomic testing for these patients and probably increase the yield of clinically relevant findings, which may ultimately improve the precision of approaches for treating many patients with cancer.”


1. Duncavage EJ, Schroeder MC, O’Laughlin M, et al. genome sequencing as an alternative to cytogenetic analysis in myeloid cancers. N Engl J Med. 2021;384(10):924-935. doi: 10.1056/NEJMoa2024534

2. Promising role for whole genome sequencing in guiding blood cancer treatment. News release. Washington University School of Medicine in St. Louis. March 10, 2021. Accessed March 26, 2021. https://bit.ly/39zChl5