Genome Sequencing More Informative than Cytogenetic Analysis in Myeloid Cancers

Genetic profiling is a routine component of the diagnostic workup for an increasing number of cancers and is used to predict clinical outcomes and responses to targeted therapies. Genomic analysis is essential for risk stratification in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS).

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. These features of whole-genome sequencing suggest that it could improve genomic profiling in patients with cancer.

A large team of scientists led by those at Washington University in St. Louis (St. Louis, MO, USA) used a streamlined whole-genome sequencing (ChromoSeq) approach to obtain genomic profiles for 263 patients with myeloid cancers, including 235 patients who had undergone successful cytogenetic analysis. The team analyzed the performance of whole-genome sequencing by comparing their results with findings from cytogenetic analysis and targeted sequencing. Sequencing was performed on NovaSeq 6000 sequencing instruments (Illumina, San Diego, CA, USA). The scientists used fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR), chromosomal microarray analyses, and RNA-sequencing data to confirm findings on whole-genome sequencing that had not been detected by cytogenetic analysis.

The investigators reported that whole-genome sequencing detected all 40 recurrent translocations and 91 copy-number alterations that had been identified by cytogenetic analysis. In addition, they identified new clinically reportable genomic events in 40 of 235 patients (17.0%). Prospective sequencing of samples obtained from 117 consecutive patients was performed in a median of five days and provided new genetic information in 29 patients (24.8%), which changed the risk category for 19 patients (16.2%). Standard AML risk groups, as defined by sequencing results instead of cytogenetic analysis, correlated with clinical outcomes. Whole-genome sequencing was also used to stratify patients who had inconclusive results by cytogenetic analysis into risk groups in which clinical outcomes were measurably different.

The authors concluded that whole-genome sequencing provided rapid and accurate genomic profiling in patients with AML or MDS. Such sequencing also provided a greater diagnostic yield than conventional cytogenetic analysis and more efficient risk stratification on the basis of standard risk categories. The authors estimated the cost of WGS, as performed in their study, to be about USD 1,900, putting it in the range of other testing platforms. At high-throughput laboratories the cost could be about USD 1,300. As the cost of sequencing decreases, WGS will likely reach price parity with conventional testing platforms. The study was published on March 11, 2021 in The New England Journal of Medicine.

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Washington University in St. Louis