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Illumina, Agilent, and NimbleGen Agree: Methylation Arrays Will Blossom in 2008

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Illumina recently announced plans to debut a 12-sample Infinium Methylation Panel in the first quarter of next year that will enable customers to assay approximately 27,000 CpG sites per sample and give the market its first “genome-wide” methylation array product.
 
The arrays will also complement Illumina’s GoldenGate methylation products that were launched in the spring for use in 96-well formats.
 
While Illumina expects its new genome-wide methylation arrays to challenge the more focused CpG island arrays currently sold by rivals Agilent Technologies and Roche NimbleGen, those companies are also prepping higher-density upgrades that they plan to launch next year.
 
Officials from all three companies said that they have seen healthy growth in the methylation array market this year, and that they expect this trend to continue into 2008.
 
Carsten Rosenow, Illumina’s senior market manager of DNA-analysis products, said the company decided to offer methylation content in a higher-throughput, 12-sample panel because of market demand for genome-wide methylation arrays as well as Illumina’s interest in making the three main areas of genetic variation — SNPs, methylation, and copy number variation — available to users involved in whole-genome association studies.
 
“[T]here’s a lot of customer interest in methylation and I think a lot of [customers] are looking for a whole-genome solution,” Rosenow told BioArray News this month. “I do believe that everyone who is doing whole-genome association studies or whole-genome expression analysis wanted to see a whole-genome panel for methylation studies.”
 
Since the first methylation arrays debuted two years ago, early adopters of the technology have generally been cancer and leukemia researchers, but Rosenow said that Illumina is now seeing interest in methylation arrays from outside these core customer bases.
 
He said that the company saw interest in the chip from “all kinds of researchers” at the American Society of Human Genetics meeting in October, where it debuted and showcased the product. “Almost everyone we asked that is doing whole-genome association studies thinks that the next step is going to be to add methylation to their analysis,” he said.
 
Rosenow added that methylation is interesting for researchers because SNPs and CNVs are “rather old mutations” that have developed over thousands of years. Methylation, in contrast, is thought to change more spontaneously, opening up a new perspective for researchers on how genomic variation impacts human health.
 
“Many people think that the combined effects of these three variations contribute to common diseases,” said Rosenow. “They want to look at them all together.” Rosenow also said that the reason the company decided to launch the GoldenGate version of the product first was to test the market and better understand the adoption rate while perfecting the Infinium methylation assay for a full commercial launch.
 
“We really want to drive this out of Illumina,” he said. “We think it has great potential, not only business-wise but for the general academic and scientific community.”
 
Agile and Nimble Rivals …
 
While Illumina prepares to launch its Infinium methylation assay in the first quarter of 2008, Agilent and NimbleGen are also readying next-generation versions of their products to serve a market that they say is growing, according to officials from both shops.
 
Rini Saxena, genomics product manager at Agilent, wrote in an e-mail that Agilent has experienced “rapid growth” in all of its methylation products, which include Human and Mouse CpG Island microarrays, Human and Mouse Promoter microarrays, and custom arrays. “Growth in CpG Island arrays has been particularly strong,” she noted.
 
Saxena said that Agilent has seen uptake from both academic and pharmaceutical customers. Most academic researchers are using the chips in cancer studies while pharma customers are studying methylation patterns to characterize disease profiles and biomarkers, she said.
 
“They’re also investigating the role of DNA methylation in X-inactivation diseases [like] Rett’s syndrome, or imprinting diseases [like] Prader-Willi [syndrome] or lupus,” Saxena said. “The reversibility of epigenetic changes has important implications for pharmaceutical manipulation.”
 

“Array-based DNA methylation is an emerging field and content frequently needs to be revised.”

According to Saxena, Agilent now plans to offer higher-density arrays with greater coverage per experiment — such as putting promoters and CpG islands on the same slide. The company is also planning to offer multiplex formats where customers can design two, four, or eight arrays per slide to reduce costs and increase throughput, and is mulling a rat CpG Island microarray.
 
Saxena said Agilent’s SurePrint array-printing technology gives it an advantage over Illumina and NimbleGen because it allows the firm to quickly create custom methylation chips and to upgrade content as it becomes available. “Array-based DNA methylation is an emerging field and content frequently needs to be revised,” she wrote.
 
NimbleGen is also planning a density upgrade to target customers doing whole-genome studies. Luke Dannenburg, the company’s epigenetics product manager, wrote this week that NimbleGen plans to expand its current DNA methylation product offering on 2.1-million-probe HD2 arrays by the second quarter of 2008 in the form of whole-genome tiling and CpG island/promoter targeted arrays. NimbleGen launched methylation arrays on its HD1 400,000-probe array format in March.
 
Additionally, to meet the high-sample demand for DNA methylation studies, the company plans to launch 12-plex DNA methylation arrays on the HD2 platform “in which all high-scoring CpG islands or customized content will be tiled per well,” Dannenburg said.
 
According to Dannenburg, cancer and developmental biology researchers are “showing the most interest” in using NimbleGen arrays to identify DNA methylated regions and patterns. There is also “considerable interest from pharmaceutical companies looking to characterize their DNA methylation-inhibitor drugs by scanning the genome for differences in methylation between treated and untreated samples.”
 
… Or Complementary Offerings?
 
By offering 12-plex arrays for whole-genome studies, NimbleGen’s product will closely compete against Illumina’s offering. But according to some researchers using methylation arrays in their studies, the market is not a zero-sum game. Instead, they claim that Illumina’s method for detecting methylation is different enough from Agilent and NimbleGen’s techniques to render the technologies complementary.
 
According to Huidong Shi, a researcher at the University of Missouri in Columbia and an Agilent user, Illumina’s approach yields higher resolution than Agilent’s and NimbleGen’s tools but requires bisulfate-converted DNA so that methylated DNA can be detected as a SNP. On the other hand, Agilent and NimbleGen’s products use monoclonal antibodies to isolate methylated DNA from the genome, which Shi argued is faster and cheaper than Illumina’s method. He suggested that a good idea for researchers would be to pair the two instead of choosing one over the other.
 
“I think they can be used together,” he wrote in an e-mail to BioArray News last week. “For instance, for the discovery study, one could use the Agilent or NimbleGen array. For the validation and targeted study, we would use the Illumina array.”
 
Izuho Hatada, a researcher at Gunma University in Japan, similarly pointed out that each technology has its pros and cons. “A merit of Illumina’s method is detection of the exact methylation position at base level, while a demerit is expensive cost,” he wrote to BioArray News last week.
 
At the same time, Hatada said that current CpG coverage on any commercially available array is not high enough for genome-wide studies. “My opinion is 27,000 CpG loci are not sufficient for genome-wide analysis,” he wrote.

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