WGS provides rapid, accurate genomic profiling for these and potentially other cancers in proof-of-concept study

In patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), whole-genome sequencing may provide quick, accurate genomic profiling, and lead to a greater diagnostic yield and better risk stratification compared with conventional cytogenetic analysis, according to results from a recent proof-of-concept study.

“Genomic abnormalities are particularly important for diagnostic classification and risk assessment in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Recurrent chromosomal abnormalities are the basis for the AML genomic classification system of the World Health Organization, and the association of these alterations and certain genetic mutations with clinical outcomes has led to the development of algorithms for genetic risk stratification in patients with AML. Similar studies involving patients with MDS have resulted in the cytogenetic component of the International Prognostic Scoring System–Revised (IPSS-R) in such patients,” according to lead author Eric J. Duncavage, MD, of Washington University School of Medicine, St. Louis, and colleagues.

Several characteristics inherent to whole-genome sequencing are conducive to improved genetic profiling in patients with cancer, they added.

“Whole-genome sequencing is an unbiased method of detecting all types of mutations and could potentially be used to replace current testing algorithms. Such sequencing can also be performed on a limited amount of DNA and can identify genomic changes that may be cryptic in other types of analyses,” they wrote in The New England Journal of Medicine.

For this proof-of-concept study, Duncavage et al used whole-genome sequencing to obtain genomic profiles in 263 patients with myeloid cancers and looked for mutations. In all, they identified 40 recurrent translocations and 91 copy-number alterations identified via cytogenic analysis.

Among the 235 patients for whom previous cytogenetic analysis was completed, clinically reportable genomic events were identified in 17.0%, including chromosomal rearrangements, gene amplifications and deletions, and single-nucleotide changes.

Among 117 consecutive patients in whom prospective sample sequencing was obtained, new genetic information was found in 24.8% of patients. This new information changed the risk category in 16.2%. When standard AML risk groups were defined by these sequencing results versus cytogenetic analysis, risk stratification correlated with clinical outcomes.

Upon survival analysis, Duncavage and colleagues found significantly longer overall survival in the 21 patients classified as having intermediate or favorable risk (median survival: 20.5 months; 95% CI, 5.6-38.8) compared with the six patients with adverse risk (median survival: 3.3 months; 95% CCI 1.7-18.9; adjusted log-rank P=0.03; and age adjusted Cox regression analysis HR: 0.29; 95% CI 0.09-0.94).

In these patients, researchers noted, the survival difference was “superior” to that corresponding with risk group assignments based on gene mutations alone.

In 11 additional patients with inconclusive results from cytogenetic analysis, stratification by whole-genome sequencing resulted in placement into risk groups in which clinical outcomes were measurably different.

“Whole-genome sequencing detected 100% of the clinically significant abnormalities that had been identified by cytogenetic analysis and clinical FISH assays. In addition, sequencing provided new genetic information in 25% of patients, more than half of whom would have been assigned to a different genetic risk category with results from conventional testing,” wrote Duncavage and fellow researchers.

The study authors noted they are confident that whole-genome sequencing for clinical testing will have direct applications not only in patients with AML and MDS, but in those with other cancers as well.

“Whole-genome sequencing can be performed on DNA from tissue biopsy samples of solid tumors, which are often insufficient for standard molecular assays and difficult to culture for cytogenetic studies. The benefits could be even greater for these cancer types, in which whole-genome sequencing could be used to rapidly survey the entire genome for an expanding number of key mutations and structural alterations with only a small amount of DNA,” they wrote.

Although larger studies are needed to validate these results, Duncavage and colleagues added that additional advantages of whole-gene sequencing include the speed of results (due to faster laboratory methods and automated data analysis), as well as decreasing costs, which they estimate to currently range from $1,000-$2,000 per patient.

“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,” Duncavage and colleagues concluded.

  1. Whole-genome sequencing provided rapid and accurate genomic profiling in patients with AML or MDS.

  2. This type of sequencing also provided a greater diagnostic yield than conventional cytogenetic analysis, as well as more efficient risk stratification on the basis of standard risk categories.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

This study was supported by grants from the Alvin J. Siteman Cancer Research Fund and the National Center for Advancing Translational Sciences and by grants from the National Cancer Institute (NCI). Support for procurement and annotation of human samples was provided by a grant from the Genomics of AML Program Project of the NCI. Core services were provided by the Alvin J. Siteman Cancer Center Tissue Procurement Core and Biostatistics Shared Resource Core through an NCI Cancer Center grant. Prospective sequencing was supported in part by reagents provided by Illumina.

Duncavage reported consulant agreements with BioReference Labs, Bristol-Myers Squibb, Cofactor Genomics, Eli Lilly and Company, as well as grants from Blumina, Alvin J. Siteman Cancer Research Fund and the National Cancer Institute.

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