Over the past year, the cytogenetics testing market has become increasingly attractive to array vendors large and small.
In March 2008, Affymetrix debuted its Cytogenetics Solution, which paired its 1.8-million-marker SNP 6.0 Array and internally developed software with the cytogeneticist in mind (see BAN 3/25/2008).
Last November, Illumina followed suit, launching its Infinium High-Density HumanCytoSNP-12 DNA Analysis BeadChip and accompanying KaryoStudio software package (see BAN 11/18/2008).
Also recently, Oxford Gene Technology and BlueGnome have released new arrays for cytogenetic use, while companies that offer array-based cytogenetic testing, like Signature Genomic Laboratories, have announced plans to expand their product lines.
During Illumina's annual Analyst Day meeting, which was webcast on Nov. 6, CEO Jay Flatley estimated the cyto testing market at about $2 billion, and Illumina expects it to double by 2012.
While the bulk of cytogenetics testing still employs fluorescent in situ hybridization and molecular karyotyping, Flatley estimated that array-based cytogenetic tests make up $200 million of the overall cyto-testing market and are growing 20 percent per year (see BAN 11/18/2008).
According to users familiar with the technology, including the heads of several cytogenetics labs, they generally welcome the breadth of available platforms. However, some say that when it comes to the new cytogenetic arrays, there is room for improvement.
For example, Brynn Levy, director of the Clinical Cytogenetics Laboratory at Columbia University in New York, said he is using Affymetrix SNP genotyping arrays for both research and clinical purposes.
"In terms of research, we use it to look for new regions of gain and loss that could potentially uncover oncogenes or tumor-suppression genes or other genes that are playing a role in the initiation and progression of the cancer we are investigating," Levy told BioArray News last week.
Levy said he is also using the arrays to help detect gains and losses in very limited specimens, like single cells. "We are looking at single cells that can be taken from circulation during pregnancy as a means to develop a non-invasive, prenatal diagnostic test, and also for pre-implantation testing," he said.
Clinically, Levy's lab uses Affy's Cytogenetic Solution as a "reflex" to G-banding, a widely used, genome-wide technique used in cytogenetics to produce a visible karyotype by staining condensed chromosomes. If a karyotype for a patient exhibiting characteristics potentially caused by a chromosomal abnormality comes back normal, Levy's lab will then perform a genome-wide analysis to search for smaller chromosomal gains and losses in the patient's genome.
"Not only can you pick up cryptic abnormalities that you cannot see by standard techniques, but we can take these gains and losses and we get very good information about the genes that are in these regions. It gives us more information about the clinical phenotype," Levy said.
Levy belongs to a smaller number of clinical cytogeneticists who have chosen to use SNP arrays as opposed to the comparative genomic hybridization approach favored by such labs as Signature, CombiMatrix Molecular Diagnostics, and Baylor College of Medicine.
Though many labs initially used bacterial artificial chromosome arrays in their services, there has been a general trend toward using oligonucleotide-based arrays in recent years, he said.
"When I moved to Columbia in 2005, people were working with BAC arrays, but I was very intrigued by Affymetrix's SNP arrays," Levy said. "I thought that the greater resolution that you could get from an oligonucleotide array would be a great asset. That is why I chose to go with oligonucleotide arrays," he added.
Levy said that data analysis continues to be a "major" challenge for his lab, but that he is encouraged by efforts made by the array vendors to improve their products, with positive results.
"There is a big financial reward if you can capture a small amount of this market," he noted. "The amount of cytogenetic tests being done per year is really significant."
Levy also said that widespread adoption of the technology by cytogeneticists is just starting to take place among the larger, better-funded academic labs.
"I think in the next five years, the majority of cytogenetic labs will have some type of array technology at their disposal," he said. "I think that cost-wise and training-wise it's a big investment and you have to get comfortable with the technology before you start offering it, but in 10 years time, I think that arrays will be [the] first line of defense, and the reflex will be to a G-banded karyotype if you need clarification."
Udo Koehler, head of cytogenetics at the Medical Genetics Center in Munich, Germany, is different from Levy in that he chose to stick with BAC arrays produced by Cambridge, UK-based BlueGnome and has so far favored the CGH approach over SNP arrays.
MGZ Munich specializes in testing pediatric patients. "In the past we did karyotyping and FISH analysis and molecular genetic testing, like [multiplex ligation-dependent probe amplification] and Southern Blot for known syndromes," Koehler told BioArray News this week.
In 2006, MGZ Munich began offering array CGH-based testing. "We have had a good experience with BACs and we haven't had the need to check through all the useless data from the oligo arrays," Koehler said. "BAC arrays are much more robust.
"BlueGnome provided us with easy-to-use software, and after two and a half years now, BAC arrays are still the arrays we use for a whole-genome screen in the beginning, after karyotyping," he said.
Koehler described MGZ Munich as an "early adopter" in Germany, but said that since 2006 most German cyto labs have also begun using the technology. "We were the first lab in Germany who offered this testing as a routine test," he claimed. "Some months later, other labs followed, and I think that everyone in Germany is aware that genetic testing without array CGH is not complete."
To round out its services, MGZ Munich recently brought in-house the Affymetrix platform. Koehler said that he does not intend to replace the BAC arrays with Affy's oligo-based arrays, but instead will use them to look at smaller deletions.
"I think that in the near future, all these tools will be used," Koehler said of the new arrays on the market. "Each lab will decide which system or platform they wish to use in respect to what the other needs of the lab are, so if some lab is doing a lot of SNP testing then, yes, they will use the Affy platform," he said. "We are happy with our mix of BAC arrays and oligo chips."
Jim Tepperberg's cytogenetics lab at Laboratory Corporation of America's facility in Research Triangle Park, NC, has also been an early adopter of array technology for cytogenetic testing.
In September 2005, LabCorp began using Spectral Genomics' BAC-based CGH arrays in its testing service. And last year, LabCorp replaced its Spectral Genomics' platform with Affy's Cytogenetics Solution to take advantage of its higher resolution, according to Tepperberg (see BAN 9/28/2005).
"Three years ago, we started with a targeted BAC array, but realized that we needed to move to a higher resolution with a genome-wide perspective," Tepperberg told BioArray News this week. "We started out initially with the Affymetrix 500K SNP platform because it gave us the greatest capability and we then moved to the SNP 6.0."
LabCorp's cyto lab typically performs routine chromosomal analysis using FISH and karyotyping for pediatric cases and for adults with reproductive issues. "Arrays combine both the genome-wide aspect [of karyotyping] plus the high resolution of FISH into a single platform that allows you to scan the entire genome, or at least targeted spots on the genome," he said.
While Tepperberg called the Cytogenetics Solution "excellent" with an "insightful" software platform, he also said that data analysis has been a challenge. "We use a database of genomic variants to assess what we consider to be the copy number variant or inherited change," he said. "We are using our own internal database and working with other Affy users to share the knowledge that we are generating."
Tepperberg said that increasing the density of current arrays would help to increase resolution even further, and that the next generation of arrays should be able to detect mosaicism, in which an individual's genome shows the presence of two populations of cells with different genotypes.
"All arrays have a difficult time assessing mosaicism right now," Tepperberg said. "We would also like to move into the oncology area and many of the hematological disorders are balanced rearrangements.
"Any array available won't detect a balanced rearrangement," he added. "There will have to be some clever ideas that will allow us to use arrays on oncology specimens."
Tepperberg said LabCorp uses its arrays for research purposes and then follows up with another technology, usually FISH or karyotyping, to confirm its results. Like Levy, he predicted that in a few years, more cyto labs will start with arrays and then move to the older techniques to confirm their findings, as opposed to how it is done today, where arrays are the "reflex" approach after G-banding has failed.
"In a few years, we may be doing arrays first and chromosomes second," Tepperberg said. "I believe that shortly arrays will be [the] primary test. How long in the future, I don't know. This will be the way we are going to do it in [the] future until high-throughput sequencing puts arrays out of business."