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Whole-Genome Sequencing Could Replace Cytogenetics in Assessing AML, Myelodysplastic Syndromes

NEW YORK — Whole-genome sequencing could serve as an alternative to cytogenetic analysis for acute myeloid leukemia or myelodysplastic syndromes, a new study has found.

For AML and MDS, genetic abnormalities — typically chromosomal rearrangements — are used to classify patients into favorable, unfavorable, or intermediate risk groups, which then informs what therapies they might be offered. The analysis is usually done through cytogenetic analysis, which can be unsuccessful for about 20 percent of patients. Researchers led by David Spencer from the Washington University School of Medicine in St. Louis analyzed whether whole-genome sequencing (WGS) could replace that conventional approach.

As they reported in the New England Journal of Medicine on Wednesday, the researchers applied a streamlined WGS approach to analyze samples from 263 patients with myeloid cancers, including 235 patients who also underwent cytogenetic analysis. They found that sequencing could quickly and accurately profile patients and at a cost approaching that of conventional cytogenetic analysis.

"We showed that genome sequencing is accurate and can detect chromosomal changes in some patients that were missed by conventional cytogenetics," Spencer said in an email. "Some of these new findings would have placed patients into a different 'risk category' using established guidelines."

Using samples from 235 patients, the researchers conducted a head-to-head comparison of conventional cytogenetic analysis and a streamlined WGS approach they developed called ChromoSeq to detect blood cancer-related alterations. According to the researchers, ChromoSeq enables comprehensive genomic profiling while limiting technical complexity and shortening turnaround time. 

Overall, sequencing analysis uncovered all 40 recurrent translocations and 91 copy-number alterations that conventional cytogenetic analysis found. In addition, for 40 patients, or 70 percent, sequencing uncovered additional genetic changes not identified through cytogenetic analysis.

Slightly less than half the samples were prospective cases who had just recently been diagnosed, the researchers noted, and for about a quarter of these cases, sequencing uncovered additional genetic information. For 19 of those patients, that added genetic information changed which risk category they fell into, which could influence their treatment options.

The prospective portion of the cohort also enabled the researchers to assess the feasibility of clinical sequencing. The samples were all successfully sequenced in batches with a median total processing time of 5.1 days.

Sequencing also had a higher diagnostic yield than conventional cytogenetic analysis, though the researchers noted that diagnostic yield would vary based on laboratory-specific practices.

Sequencing and cytogenetic analysis agreed on risk-group assessments nearly 90 percent of the time. But sequencing could inform group assignments for some patients who had inconclusive results from cytogenetic analyses. Most of the patients whose risk assessment changed based on sequencing results were placed into less favorable categories.

The researchers noted that cost has been a key barrier in the adoption of WGS in the clinic. The cost of their approach — including reagents, technical labor, and analysis — is about $1,900 with a list price of $11 per Gbp of sequence data and could drop to $1,300 in a high-volume laboratory with a cost of $7 per Gbp. They estimated that when sequencing costs less than $5 per Gpb, it would be about the same price as conventional testing.

Spencer added that he and his colleagues are starting a clinical study at their hospital to offer genome sequencing for AML patients to further assess if it could replace conventional testing methods, as well as testing their approach on other cancer types.

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