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Importance of Chromosomal Microarrays

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Illumina already had multiple chips on the market for use in constitutional and cancer cytogenetic testing as well as its own internally developed data analysis platform, KaryoStudio, when it snatched up Cambridge, UK-based BlueGnome for an undisclosed sum in September, gaining Blue-Gnome's widely used BlueFuse software in the deal as well as its range of CytoChips, which are used in everything from prenatal testing to screening embryos prior to implantation in in vitro fertilization cycles.

Other companies that sell chromosomal microarrays and array-based tests also say that demand will continue to grow, especially as array-based prenatal testing becomes more widely accepted and arrays are adopted by greater numbers of cancer cytogenetics laboratories. Affymetrix, for example, expects that sales of its main cytogenetics offering, CytoScan HD, will constitute about 10 percent of its revenues by year end. Combi-Matrix Diagnostics is also anticipating a "major shift" toward the use of chromosomal arrays in prenatal testing following the anticipated publication of the results of a five-year, National Institutes of Health-sponsored study that determined that arrays were more informative than traditional microscope-slide-based karyotyping.

'Standard of care'

The adoption of chromosomal microarrays has been due to both technology innovation and community organization and lobbying. The first chromosomal microarray services relied on lower-density bacterial artificial chromosome-based chips manufactured in house or by companies like Spectral Genomics, which was later acquired by PerkinElmer.

But interest from vendors has led to the availability of customizable, higher-density oligonucleotide arrays that first have been used for postnatal cases and now in prenatal testing.

One organization that has made this shift from older, microscope-based techniques to high-density oligo microarrays possible is the International Standards for Cytogenomic Arrays consortium. Founded in 2007, the group of clinical cytogenetics and molecular genetics laboratories works to set community guidelines for array design as well as data interpretation, patient counseling, and data sharing.

In May 2010, ISCA published a statement in the American Journal of Human Genetics that recommends using arrays as "first-tier" tests to assess individuals with unexplained developmental delay and intellectual disability, autism spectrum disorders, or multiple congenital anomalies. To support the statement, ISCA conducted a literature review of 33 studies, including nearly 22,000 patients tested by chromosomal microarrays, to provide an evidence-based review that compared chromosomal micro-arrays to G-banded karyotyping.

Following that publication, the American College of Medical Genetics and Genomics revised its guidelines to recommend that chromosomal arrays be used instead of G-banded karyotyping as the first test to detect genetic abnormalities in post-natal evaluations. And in 2011, ACMG published recommendations for how best to design and interpret chromosomal microarrays used in clinical labs. In three years, ISCA had accomplished one of its main goals as an organization.
"I think we nudged the college to come to the recommendation that they did," says David Ledbetter, an ISCA co-founder and chief scientific officer at Geisinger Health System in Danville, Pa. "In my view, this is the new standard of care in the United States," he adds.

In some ways, ISCA's role in moving professional organizations like ACMG to revise their guidelines, is the new pattern by which other groups, many of them linked through membership with ISCA, have sought to have array-based prenatal testing and cancer cytogenetic testing become more widely accepted.

In the prenatal arena, a $5.5 million study funded by the National Institute of Child Health and Human Development may lead to revised guidelines. The project saw researchers at Emory University, Columbia University Medical Center, Baylor College of Medicine, and Signature Genomics Laboratories use arrays from Agilent Technologies and Affymetrix as well as traditional karyotyping for comparison, on more than 4,000 cases.

According to study researchers, arrays detected additional abnormalities in one out of every 70 fetal samples that had a normal karyotype. And when a birth defect was imaged by ultrasound, arrays found relevant genetic information in 6 percent of cases, results that led the team to conclude that arrays are more informative than standard, microscope-based karyotyping to identify genetic abnormalities in prenatal cases. The group is expected to publish a paper on the findings by the end of this year.

Ledbetter says it is likely that the study results will lead to some revision of current guidelines concerning prenatal testing. "I think the study is large enough to influence current guidelines and to inform that process in an important way," he says. Current ACMG guidelines are to only use chromosomal microarrays as an adjunctive test.

However, he cautions that chromosomal microarrays may become a first-tier technology only in select cases. "Some proportion of the people in the US and on the European side are mainly focused on pregnancies with abnormal ultrasounds, fetuses with structural abnormalities, for which the published data has already shown a high yield by chromosomal microarray," Ledbetter says. "A limited introduction of chromosome microarray would be only those pregnancies where you have an ultrasound abnormality and a normal karyotype."

'Incidental findings'

Though chromosomal arrays can detect a higher frequency of genomic imbalances, geneticists are sometimes unsure of what those variants mean in a clinical context.

According to Richard Choy, an associate professor of obstetrics and gynecology at the Chinese University of Hong Kong, arrays should replace karyotyping as a first-tier test for prenatal diagnostics based on their detection capabilities. At the same time, he says that questions surrounding array technology make it unpopular. One of these questions is the issue of correlating genotypes to certain phenotypes. Another is the existence of copy-number variants of unknown significance. "Once these two issues have been solved, I am sure people will use arrays because we really have increased the detection rate of pathological copy-number variants," he says.

Dom McMullan, head of molecular cytogenetics at the West Midlands Regional Genetics Laboratory in Birmingham, UK, says that things are proceeding at a slower pace in the UK than in the US because of these issues. According to McMullan, UK labs are currently looking to adopt chromosomal arrays only in pregnancies with an abnormal ultrasound scan. He says that there is an ongoing seven-center study funded by the National Institute for Health Research that, upon conclusion, is likely to inform best practices in the UK.

"Reporting findings of unclear clinical significance has been a difficult area since the introduction of prenatal diagnosis by chromosome analysis," McMullan says. "It is not really a new problem, just likely to be more common with use of arrays and at a different level of resolution."

Ellen van Binsbergen, a clinical cytogeneticist at University Medical Center Utrecht in The Netherlands, says that some cytogenetists are apprehensive about offering chromosomal micro-array analysis for lower-risk indications, such as advanced maternal age. "You are going to wonder what happens if you encounter one of those autism-associated regions and you don't know if it is going to result in a phenotype," van Binsbergen says. "So I think we should be aware of what indications you should allow to test for."

To overcome the challenges of interpreting these findings and relaying the results back to clinicians and on to patients, geneticists are relying on a number of data-sharing resources. ISCA maintains a database of whole-genome array data from clinical diagnostic laboratories. More recently, the Cytogenomics Array Group developed the CAGdb database to share data related to abnormal microarray findings.

According to Hutton Kearney, director of the cytogenetics laboratory at the Fullerton Genetics Center at Mission Health in Asheville, NC, that hosts CAGdb, clinical laboratories and researchers are "desperate" to curate and access information connecting rare genotype to phenotype. "We are making great progress," she says, "but much genomic variation remains to be understood."

Cancer cytogenetics

While chromosomal arrays have become the standard of care for constitutional cytogenetic testing and may become more widely used in prenatal testing, their penetrance into cancer cytogenetics labs is still limited.

Anwar Iqbal, president of the Cancer Cytogenomics Microarray Consortium and the head of the microarray CGH lab at the University of Rochester Medical Center in New York, says that according to an internal survey of the CCMC's 300 or so members, about 45 percent of them are using chromsomal microarrays for clinical testing, though he says the percentage is increasing.

As an organization, the two-year-old CCMC is arguably off to a good start. An initial quality control study that compared the ability of participating laboratories to obtain the same results from the same samples using different array platforms concluded last year. Meantime, CCMC members have helped draft guidelines on using microarrays in clinical cancer cytogenetics that are making their way through the ACMG approval process.

And perhaps sensing a new opportunity, vendors have been quick to debut new products. Oxford Gene Technology, for instance, recently launched an oncology-focused comparative genomic hybridization-plus-SNP chip. Designed in collaboration with Jacqueline Schoumans, head of the cancer cytogenetics unit at the University of Lausanne in Switzerland, OGT's new array contains content relevant to hematological malignancies and solid tumors. The company also sells a chip focused solely on hematological cancers and is planning a third offering based on the CCMC's gene list. Agilent, Affy, Illumina, and other vendors have similarly positioned their arrays for use in cancer cytogenetics with some, like fresh Illumina acquisition BlueGnome, debuting a number of focused chips for the burgeoning market.

"We are trying to answer the same kinds of questions, basically, but in cancer cytogenetics we are a couple of years behind," Schoumans says.

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