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Study Shows Prognostic Significance of Loss of Heterozygosity in AML, Supports Array-based Testing

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NEW YORK (GenomeWeb) – In a new study, researchers from the Fred Hutchinson Cancer Research Center have demonstrated that copy-neutral loss of heterozygosity has a clear and independent prognostic significance in patients with acute myeloid leukemia.

The data, published recently ahead of print in the journal Cancer, also support the clinical utility of array-based approaches, which can detect these genomic features in addition to better established markers like copy number alterations.

Min Fang, the study's senior author and director of cytogenetics at the Seattle Cancer Care Alliance, told GenomeWeb that she and her team hope the publication will help promote recognition of the utility of testing for cnLOH by larger professional societies and guidelines, which have not yet adopted cnLOH into their recommendations for the clinical assessment of AML.

The reason professional groups have not yet promoted testing for cnLOH, Fang said, is that the genomic array technologies that detect it have only recently been incorporated into clinical AML testing.

"Up till very recently there was not a good way to even detect these abnormalities," she said. "But now the new genomic techniques allow us to detect this, so the question arises, 'Now that we can detect it, and we have seen that it is fairly commonly observed, what does it mean?'"

While previous studies have also demonstrated that cnLOH can provide additional prognostic information to other markers, most of these have been conducted in the research setting.

Fang said she and her colleagues' study of data from actual clinical practice provides an additional solid layer of support to previous findings.

More specifically, the team's results showed that patients with intermediate risk, based on cytogenetic testing, may benefit especially from the additional prognostic information provided by chromosomal genomic array testing (CGAT) that includes measurement of cnLOH.

In their study, the researchers looked at 112 consecutive clinical AML cases who underwent CGAT at Fred Hutch between 2009 and 2013, and who had clinical, pathological, and outcome results available.

Patients were evaluated at the center using Affymetrix's CytoScan HD, a high-density microarray containing 2.5 million markers including 750,000 SNPs, the authors wrote.

When the investigators analyzed the clinical and outcome data for these patients in light of the presence or absence of cnLOH, they found that it had a significant effect on the cumulative incidence of disease recurrence, with a hazard ratio of 1.87.

In addition, the team reported that patients with cnLOH specifically affecting chromosome 13q had more than a six-fold higher rate of disease recurrence and a more than three times greater risk of death, confirming earlier results from research populations. This prognostic link was also independent of patients' age and cytogenetics.

The median overall survival for the 40 patients in the cohort with measurable cnLOH was 11 months versus 12.9 months in those without cnLOH. Finally, although disease recurrence and survival worsened progressively for patients with greater numbers of chromosomes affected by cnLOH, this was not independent of other covariates.

The researchers also looked further, ranking the effect of cnLOH in individual chromosomes with therapeutic complete response rates. CR was worst in the context of cnLOH of 9q, 17p, and 19q, and best in the context of cnLOH in 1p, 2p, and 21q, they wrote. However, more cases and independent studies will be needed to validate these findings.

Comparing cnLOH and cytogenetic risk factors, the group also saw that as cytogenetic risk worsened, the difference in CR rate between patients with and without cnLOH increased.

Overall, they found that the greatest effect of cnLOH independent of cytogenetics was in patients in the intermediate cytogenetic risk group, which is clinically promising, Fang said.

"The favorable and poor prognostic groups are already well characterized, but in the intermediate-risk group, which is more than 50 percent of AML patients, that's the group where we really need better prognostic classifications and where cnLOH can really help," she explained.

Beyond analyzing the prognostic impact of cnLOH, the study also showed that a complex CGAT result is associated with relatively poor outcomes, similar to a complex karyotype based on conventional cytogenetic testing.

Fred Hutch and many other centers have been incorporating CGAT into their clinical assessment of AML patients for several years, Fang said, in order to measure other markers, mainly copy number alterations, which have been shown to impact disease severity and prognosis.

Fang and her colleagues now hope that their study can help better demonstrate that cnLOH, which is also measurable using these array technologies, has added utility in clinical practice and should join these other markets in the landscape of prognostic measures.

"We have been using this to detect copy number aberration, and those … have been well established in terms of their prognostic, and diagnostic utility," she said. "We are now promoting that since you are now using these technologies and you are able to see these additional abnormalities with their own prognostic significance, we should also use that as a patient management tool."

She added that she and her coauthors are now preparing to publish a follow-up study focused specifically on the impact of cnLOH in the cytogenetics intermediate-risk group.

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