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A New Niche for Arrays


This article has been updated to clarify that Dara Wright, vice president of clinical marketing at Affymetrix, is female.

As many cancer researchers move beyond microarrays and on to advanced sequencing technologies for their investigations, a small but growing group of oncologists and cytogeneticists seek to secure a new niche for arrays in the clinical setting. Before 2009, Anwar Iqbal, Marilyn Li, and Charles Lee had all been working individually to design cancer-specific cytogenetic arrays, each with limited success. After the Vector Biotechnologies Midwest Microarray Meeting that August, and inspired by the International Standards for Cytogenomic Arrays Consortium's postnatal cytogenetic array, the three researchers decided to pool their resources. Together, they established the common goal of designing platform-neutral, cancer-specific arrays for clinical use; they also agreed to share the data they generate using these chips and to create a public repository for that information — all in an effort to facilitate future translational research.

Iqbal, an associate professor of pathology at the University of Rochester in New York, says the Cancer Cytogenomics Microarray Consortium came together naturally. The trio quickly realized it'd be best to "combine, concentrate, and focus together ... for the community," he says.

Lee, an associate professor of pathology at Harvard Medical School and clinical cytogeneticist at Brigham and Women's Hospital, says the consortium also serves as a collective sign of support for array-based clinical oncology tests. "The time was ripe for a concerted effort to approach the issues each of us were facing with different array designs," he says. "It was gratifying to see that there were a growing number of people that were interested in using arrayCGH for clinical diagnostics."

Indeed, the consortium has amassed an impressive membership, given that it has only been around for two years. At present, CCMC has more than 250 members at more than 104 institutions. In addition, the group's efforts have attracted substantial participation and financial support from industry. "The vendors have been really anxious to participate and very supportive," says CCMC member Jaclyn Biegel, professor of pediatrics at the Children's Hospital of Philadelphia. "The whole CCMC group has really grown over the last year-and-a-half: we had 100 people at last summer's meeting. ... We had a meeting in the fall that had a huge turnout, so people are really interested."

To prove a point

Biegel says some researchers have recently called the adequacy of arrays into question. "There's been a lot of discussion in the literature — and among different laboratories — about whether these array technologies are ready for primetime for oncology," she says.

To assuage those worries, the consortium established a quality assessment and quality control arm, which is now initiating a series of clinical trials to evaluate the group's array designs on Affymetrix, Agilent, and Illumina platforms. "This is really an effort to convince the [array] skeptics," says Biegel, who is directing the trials at CHOP.

To determine the clinical validity of CCMC's array designs, researchers at six academic institutions are running de-identified clinical chronic lympho-blastic leukemia, myelodysplastic syndrome, and renal cell carcinoma samples — chosen to represent a variety of malignancies — on their respective array platforms and comparing the results they generate with those they obtain when performing standard chromosome analysis and fluorescence in situ hybridization assays on them. All samples will be analyzed in three to four replicates to assess intra-lab reproducibility; they will also be run on the same array platform at another lab in order to validate inter-lab reproducibility.

"After CCMC members collect more data, we expect that the array design will be further refined," says Anniek De Witte, CGH microarray product manager at Agilent. "We also envision that different labs could use different CCMC designs," she says, adding that the firm expects the consortium's trials "will demonstrate great concordance between labs and between technologies."
Dara Wright, vice president of clinical marketing at Affymetrix, adds that the firm is "committed to evolving microarray technology for clinical applications, so contributing to the CCMC initiative is very important to us."

To date, CCMC has developed two versions of its array: CCMC-v1 screens for cancer-associated copy number changes and CCMC-v2 interrogates copy neutral alterations as well as CNVs — an important addition, as "copy neutral losses are a common feature of cancer," Iqbal says.

To power translation

While the standard model of translational research — that the bench informs the bedside — has enabled improvements to oncology diagnostics, prognostics, and therapeutics, CCMC proposes a more synergistic relationship between the lab and the clinic. "It's clear that with cancer research progressing as fast as it is right now — some of it spearheaded by the fact that more centers are actually whole-genome sequencing cancers and finding biomarkers — when you can identify those biomarkers on genotyping arrays, then it's definitely something we should add" to clinical care, Harvard's Lee says.

Because of technological improvements, Lee says clinical results can also influence basic research. "It's a wonderful circle that when you get more information on the genetics of these cancers through the clinic, often you'll start to uncover interesting trends that you wouldn't have noticed before, and you'll be able to group samples based on genotypes that you'd missed by cytogenetics before as well," he says. "That could feed into the identification [and] re-classification of different subtypes of cancer. There's a sort of feedback loop from the clinic back to basic research: once you have more information on those precious samples, those can go, in an IRB-approved manner, to the research setting for further workup."

Whether that's eventually the case, Rochester's Iqbal says CCMC is working to fill a critical need in cancer cyto-genetics. "For clinical application, it's very important that the product or the test which we use should be a universal test, because when we can find something in one lab, it should be replicated in other labs," he says.

Harvard's Lee is hopeful that CCMC will develop an array that "will very quickly make much more accurate diagnoses than what we currently have with conventional cytogenetics." He points to congenital disorders as an example of how that could eventually become the case, as he says arrayCGH has replaced conventional karyotype testing in this arena. "My prediction is that something similar is going to happen with the cancer field: cytogenetics labs that are doing cancer diagnostics are going to find that the arrays will get you diagnostically important information quickly, [with] less subjectivity than chromosome analysis, and will also give you stuff that the G-band analysis just won't pick up, including loss of heterozygosity, and smaller gains and losses [of] less than 5 megabases," Lee says. "I wouldn't be surprised that once more people use it and the data is collected that there will be a white paper drafted by the College of Medical Genetics or another respective body, saying 'It's our recommendation that arrays are the first line of defense for cancer cytogenetic diagnostics.' That's what I see in the future."

The Breakdown
Members: More than 250 members at 104-plus institutions in Brazil, Canada, Switzerland, the UK, and the US.
Funding: Anwar Iqbal and Marilyn Li were co-PIs on a one-year, $100,000 American College of Medical Genetics Foundation/Luminex Corporation grant that provided startup support for the consortium in 2010; Affymetrix, Agilent, and Illumina all provide the arrays for the trials and contribute financial support for the group's annual meetings.
Timeline: Established in 2009.

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