Instrument companies appear to be gearing up to expand their microarray offerings into regulated markets. So far this year, three companies have made announcements regarding FDA 510(k) submissions of their cytogenetic microarray products. And just this week, PerkinElmer purchased a provider of clinical cytogenetic microarray testing services (see page 2). The news illustrates the rapid extension of new life science research techniques into clinical applications, as well as instrument companies’ role in developing such technologies for homebrew and regulated clinical markets.

Cytogenetics is the study of chromosomal abnormalities, which are caused by alternations in the number or structure of chromosomes. Chromosomal-related conditions include mental retardation, congenital disorders and reproductive problems. Cytogenetics is also a component of cancer diagnosis and treatment.

Compared to earlier molecular clinical cytogenetics techniques such as FISH (fluorescence in situ hybridization), array-based CGH (comparative genomic hybridization) provides higher resolution and faster throughput for detection of copy number variation (CNV). For clinical cytogenetics, CGH arrays include BAC (bacterial artificial chromosome), oligonucleotide and, most recently, SNPs and oligos. Oligo CGH arrays have surpassed BAC arrays to become the dominant arrays for clinical cytogenetics. According to a 2009 paper by Yiping Shen, PhD, published in Clinical Chemistry, the advantages of oligo CGH arrays compared to BAC arrays include higher resolution and sensitivity, greater reproducibility and reliability, and easier customization for specific chromosomal regions. Major provides of oligo CGH arrays for cytogenetics are Agilent, Roche NimbleGen and Oxford Gene Technology, whose products are manufactured by Agilent. Clinical labs, such as Signature and Baylor College of Medicine, offer their own oligo CGH arrays for homebrew clinical cytogenetics testing. Signature’s arrays are produced by Roche NimbleGen, while Baylor’s offerings are based on Agilent technology.

Illumina and Affymetrix offer SNPs/oligo arrays for cytogenetics. These arrays can detect CNV as well as loss of heterozygosity. Asked about clinical diagnostic labs’ use of SNP/oligo microarrays, Gregory Heath, PhD, senior vice president and general manager of Diagnostics at Illumina, told IBO: “Recently, an increasing number of labs are looking to implement Infinium SNP arrays due to their strength in unambiguously identifying copy number changes, in addition to their unique advantage in detecting low-level mosaicism and copy neutral events, such as uniparental disomy, autozygosity, and consanguinity.”

Illumina announced in January that its plans to submit products to the FDA using the preliminary investigation device exception. Under this process, a company can receive feedback about its product and a clinical study can be undertaken that will be used to support a submission for premarket approval or premarket notification 510(k) approval. Illumina’s products for cytogenetics include the HumanCytoSNP-12, HumanOmni1-Quad, Human660W-Quad and Human1M-Duo BeadChips, KaryoScan and Genome Studio software, and the iScan reader. Dr. Heath foresees microarrays replacing half of the FISH-based cytogenetic testing market by 2015.

Dr. Heath told IBO that Illumina plans to pursue FDA 510(k) clearance for the iScan reader, and the Infinium Assay on the HumanCytoSNP-12 and HumanOmni1-Quad BeadChips. “Laboratories that have evaluated the safety and efficacy of microarrays have advocated its readiness for use in the clinic,” he said. “Reports have predicted that the diagnostic yield will be significantly greater when using microarrays, meaning more patients will have a clear answer more quickly. Which, in this case, supports early diagnosis and improved diagnostic precision that will lead to specific decisions for therapy and long-term preventive care.” The HumanCytoSNP-12 is designed for the routine screening of common cytogenetic abnormalities and contains approximately 300,000 markers, including those for 250 of the most commonly affected genomic regions. With 1.1 million markers per sample, the HumanOmni1-Quad is designed for CNV discovery.

Although Affymetrix has not made any recent announcements regarding 510(k) plans for its SNPs/oligo cytogenetic arrays, the company has consulted with the FDA regarding a regulated product, according to President and CEO Kevin King. “Our good standing with the FDA has allowed us to market the only FDA-cleared microarray instrument, the GeneChip System 3000 Dx, for diagnostic applications,” he told IBO. “We believe this experience, combined with the ability to reliably and easily detect chromosome abnormalities, gives us an excellent opportunity to continue development of FDA-cleared tests. While we are actively pursuing discussions with the FDA regarding future cytogenetics-related clinical applications, we cannot predict what decisions the FDA will make regarding timing.” Last year, Affymetrix introduced the Cytogenetics Whole-Genome 2.7M Array, with 2.7 million markers and 400,000 SNPs, and the Cytogenetics Focused Array, with more than 330,000 markers.

In March, Agilent announced that its microarray manufacturing achieved ISO 13485 certification, which certifies it for medical device manufacturing. In the announcement, Gustavo Salem, Agilent vice president and general manager, Biological Systems, stated: “We believe that Agilent is in a strong position to take the next step in our dialog with the US FDA toward pursuing clearance for a cytogenetics device based on Agilent’s platform.” Agilent declined to disclose to IBO the cytogenetic products for which it would pursue 510(k) clearance, but Robert Schueren, Agilent’s vice president and general manager, Genomics, stated, “we have met with the FDA in the past specifically about the cytogenetic field.” Agilent’s cytogenetic CGH offerings include the SurePrint G3, HD-CGH and custom CGH microarrays. The SurePrint G3 Human CNV Microarray Kit 2 x 400K is a genome-wide array for characterizing known CNV regions.

Roche NimbleGen recently announced that it has begun an initiative to implement GMP for its microarrays, which will be followed by submission of certain array products to the FDA. Dr. Andreas Görtz, vice president of Marketing, stated that, “cytogenetics is one of the first areas where there is interest to move beyond the current research studies, which will require an FDA cleared or approved product.” Roche declined to be interviewed for this article. Last year, the company released the NimbleGen CGX cytogenetic microarrays. These arrays, designed by Signature Genomics, feature up to 2.1 million probes and are supported by Signature’s Genoglyphix software. The company also offers 2.1M and 3x720K CNV arrays, as well as CGH Whole-Genome Tiling Arrays, exon-focused arrays and custom CNV targeted arrays for cytogenetic CGH.