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European Study Notes Growing Use of Arrays over Karyotyping in Routine Hematological Cancer Diagnosis

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While microarrays are quickly replacing traditional karyotyping in constitutional cytogenetic testing, the technology is also beginning to displace conventional methods for the clinical diagnosis of hematological cancers, according to a report by researchers from several European medical centers.

Led by researchers at Radboud University Nijmegen Medical Center in the Netherlands, the group discussed in a review appearing in the journal Human Mutation this month how comparative genomic hybridization and SNP arrays for “molecular karyotyping” have overcome some of the limitations of conventional karyotyping methods for the monitoring of leukemia and other hematological malignancies.

Jacqueline Schoumans, the study’s senior author, told BioArray News that array analysis, whether by CGH or SNP arrays, has steadily begun replacing conventional karyotyping for a number of indications in clinical cancer diagnosis and prognosis. Schoumans is head of the Cancer Cytogenetic Unit at Lausanne University Hospital in Switzerland. Researchers at the University of Groningen in the Netherlands and Radcliffe Hospital Women's Center in Oxford, UK, also contributed to the review.

Schoumans said the review was the result of a workshop organized at the European Society of Human Genetics 2011 annual meeting, which spurred the overview as a way of better publicizing the advantages and discussing the challenges of the growing use of arrays in the field of onco-hematology.

Hematological cancers have traditionally been managed using conventional karyotyping with targeted fluorescence in situ hybridization, the group wrote in its report. But the advent of SNP and CGH microarray-based copy number and genotype analysis offers the ability to identify very small copy number aberrations at higher accuracy than conventional karyotyping.

Though it has been challenging to implement molecular karyotyping in the hematological cancer diagnostic setting, the researchers wrote, the method’s added clinical value and cost-effectiveness have begun to manifest in the diagnosis and treatment of a number of hematological diseases, including chronic lymphocytic leukemia, myelodysplastic syndrome, multiple myeloma, acute lymphoblastic leukemia, and acute myeloid leukemia.

According to Schoumans, use of array-based karyotyping is growing mostly in hematological malignancies for which deletions and duplications have already been reported to have clear prognostic impact, such as CLL and MM rather than AML or ALL, which involve balanced translocations. When searching for recurrent balanced translocations FISH tests or translocation CGH have to be added, she explained.

Schoumans said that array analysis "has an advantage" over conventional karyotyping and FISH for accurate location and size mapping of specific deletions, which have prognostic implications. "For example, the deletions at locus 13q14 in CLL can be divided into class one or class two deletions, depending on the size of deletion," she said. "Class I deletions have been reported to have a more favorable prognosis compared to class twos."

Schoumans said that her laboratory at Lausanne University Hospital is the largest cancer cytogenetic lab in Switzerland and has validated different types of array platforms in onco-hematology.

"We have [now] completely replaced conventional karyotyping and FISH panels [with] array diagnostics for prognostic assessment of chronic lymphocytic leukemia … and we are currently validating its usefulness in other types of leukemia," she said.

According to Schoumans, the usefulness of arrays in this area and their sensitivity to detect low-concentration variations has been underestimated, while cost has been overestimated. "[But] with the development of commercially available arrays and the multiplex arrays … the costs per sample have dropped significantly over the past [several] years," she said. "Our experience shows that array analysis can be cost effective."

In the Human Mutation review, Schoumans and her coauthors discuss the relative benefits and weaknesses of CGH and SNP arrays for this type of analysis.

According to the group, CGH arrays enable sensitive detection of small copy number variations in a low proportion of cells — low-grade mosaicism. CGH arrays also allow for customization to densely cover select genes or loci of interest.

However, the authors contend that CGH arrays do not allow detection of copy neutral loss of heterozygosity or the identification of recurrent balanced chromosomal rearrangements.

SNP arrays, meanwhile, can detect copy number variations and copy neutral loss of heterozygosity simultaneously, but have been reported to be "somewhat less sensitive" for identifying low-grade mosaicism and are less flexible for custom targeted design, Schoumans said. SNP arrays also can’t identify balanced chromosomal rearrangements.

In the report, the group also discussed combined arrays that incorporate both CGH and SNPs, as well as translocation arrays.

Overall, they wrote, array-based molecular karyotyping can offer deeper, more sensitive analysis, as well as a simplified system as compared to karyotyping or FISH.

"With the identification of novel loci/genes with prognostic implications in cancer the number of loci to be included in routinely used FISH panels has increased," Schoumans wrote. "But when replacing large FISH panels by arrays the whole genome is interrogated in one assay."

In addition to adopting array-based karyotyping for CLL in her laboratory, Schoumans said her group is also planning to replace large FISH panels for multiple myeloma with arrays by the end of the year.

Also, she told BAN via e-mail, "for myelodysplastic syndrome we perform array analysis on request to screen for small deletions on the long 5q arm of chromosome 5 since some health insurances will only reimburse a treatment with lenalidomide when a deletion has been identified. Such small deletions could be missed when using conventional cytogenetics only."

Schoumans is a member of the Cancer Cytogenomic Microarray Consortium, which has said it is supporting a variety of studies it hopes will speed the adoption of arrays in clinical cancer cytogenetics. (BAN 12/6/2011)

According to Schoumans and her coauthors, guidelines for standardized data interpretation would be needed for widespread routine clinical use of array-based karyotyping. In their review, the researchers highlighted a workflow for practical diagnostic use in ALL proposed last year in Genes, Chromosomes & Cancer by a Dutch group including one of Schoumans’ co-authors.

Another key issue for growing adoption of array-based karyotyping is reimbursement by different healthcare systems, according to the group. Schoumans said she believes that the use of arrays for clinical karyotyping in hematological cancer may be more widespread in the US than in Europe. In the US, she noted, a number of private laboratories offer such testing, but in Europe, the clinical use of array-based karyotyping is more limited to those countries where health insurance reimburses for the analysis.

Several companies are offering arrays intended to replace or augment conventional karyotyping and FISH in hematological cancer analysis. Ambry Genetics and Signature Genomics have both launched panels in the space (BAN 9/13/2011) as has Oxford Gene Technology with its CytoSure Hematological Cancer +SNP array, a combines SNP and CGH chip (BAN 3/6/2012).