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Cancer Cytogenomics Microarray Consortium Aims to Set Standards for Arrays in Cancer Dx

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By Justin Petrone

Looking to spur the adoption of microarray technology for the diagnosis of cancer, the Cancer Cytogenomics Microarray Consortium will carry out next year a multicenter, multi-platform validation study to demonstrate that the new technology is reliable and reproducible enough for clinical use in cancer diagnostics.

The CCMC is also advancing a consensus design of what content should be included on all cytogenomic arrays that are used in cancer testing, according to members of the CCMC's steering committee. Cytogenomic arrays have been widely applied in constitutional testing, and the organization now seeks to enable the judicious use of microarray technology in clinical cancer cytogenetics.

The CCMC was formed last year by a group of clinical cytogeneticists, molecular pathologists, and molecular geneticists who are interested in applying microarray technologies to cancer diagnosis and cancer research. According to its website, the CCMC aims to set up platform-neutral standards for cancer microarray designs and to create cancer-specific platforms suitable for cancer diagnosis, to share cancer microarray data, to create a public cancer array database, and to carry out multicenter cancer genome research.

Jill Hagenkord, who sits on the CCMC's steering committee, told BioArray News this week that the organization will begin its validation study in January. "We want to show that this technology is safe, reliable, reproducible, and robust for clinical use," she said. "No matter what vendor's platform you are using or what laboratory you are sending your samples to, you should be able to get the same diagnostic line from all of us."

According to Hagenkord, who is medical director of the Molecular Pathology and Clinical Genomics Laboratories at Creighton Medical Laboratories in Omaha, Neb., and the founder and chief medical officer of startup iKaryos Diagnostics, the validation study will be conducted at six labs on three microarray platforms.

Specifically, samples will be run on the Affymetrix platform at Creighton and Columbia University; on the Agilent Technologies platform at Baylor College of Medicine and the University of Medicine and Dentistry of New Jersey; and on the Illumina platform at the Children's Hospital of Philadelphia and the Medical University of South Carolina. All of the labs are compliant with the Clinical Laboratory Improvement Amendments.

Each lab will evaluate the ability of the platforms to detect chronic lymphocytic leukemia, myelodysplastic syndromes, and renal cancer in fresh solid and formalin-fixed, paraffin-embedded tumors. These results will then be compared against "gold standard assays," Hagenkord said, such as fluorescence in situ hybridization, conventional karyotyping, and morphology.

The CCMC aims to submit a manuscript about the clinical validation study for publication by the third quarter of 2011, with the hope that the information contained will contribute to the setting of new guidelines by professional societies, such as the American College of Medical Genetics, which could recommend the use of arrays in cancer cytogenetics, Hagenkord said.

She likened the study to the Microarray Quality Control project, in which a US Food and Drug Administration-hosted consortium demonstrated concordance in expression data across major array platforms using two RNA reference samples. "It will show that different platforms and technologies at different institutions, if run with tight standard operating procedures, will get the same reliable, reproducible results," Hagenkord said.

Besides the MAQC, another organization that has inspired CCMC is the International Standard Cytogenomic Arrays consortium. Many of the CCMC's 240 members are also ISCA members. Last May, ISCA published a consensus statement urging the adoption of microarrays as a first-line test for detecting congenital abnormalities (BAN 5/18/2010). In September, ACMG revised its guidelines to recommend that cytogenomic arrays be used as first-tier diagnostics in assessing patients with such conditions, leading ISCA head David Ledbetter to call cytogenomic arrays the "new standard of care in the United States" (BAN 9/28/2010).

Hagenkord said that CCMC's cancer array standards and guideline committee is working with counterparts at the ACMG to draft future guidelines. Once recommendations are in place, Hagenkord predicts that the adoption of arrays in cancer cytogenetics, which has grown more slowly than it has in constitutional genetics, will rise. "Once the standard guidelines come out, it's going to go very quickly," she said.

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Standard of Design

Another project underway is the design of a standard array for use in cancer diagnosis. Marilyn Li, a member of the CCMC steering committee and director of the Cancer Genetics Laboratory at Baylor, told BioArray News this week that the group is currently working with Agilent Technologies to design such a cancer-specific array.

According to the CCMC's website, the current version of the array contains 500 cancer genes and more than 130 cancer-associated genomic regions have been selected to build the chip. The cancer genes are separated into two groups: well-defined cancer genes commonly involved in different cancers, and those that are relatively new members of the cancer gene family.

The Agilent array includes about 20,000 cancer-associated probes while the remaining probes are relatively evenly distributed throughout the genome as the backbone. Six arrays, each containing four subarrays of 40,000 probes, were printed and are being checked, according to the CCMC. Designs for 8x60K and 4x180K are also done and will be printed to compare with the 4x44K design.

"The CCMC cancer-specific array targets cancer genes as well as regions that we know are related to cancer and also covers the backbone," said Li. "It's a whole-genome array with focused areas." According to Li, the design of the array is "primarily done" and will be completed next year. The organization makes the array design available to members, so long as they agree to share the data and not sell the arrays as their own product. Li said that about 15 labs currently have access to the CCMC array.

While the original design has been done with Agilent, the CCMC is providing the content to Affy and Illumina. "The standard of design is not going to be one design," Li stressed. "It's the content that should be on every cancer array."

Hagenkord, for instance, is working with Affy’s off-the-shelf arrays, both 250K Nsp and SNP6.0, for all arms of the upcoming validation study. She said the outcome of the validation study may also inform the creation of next-generation cancer arrays for Affy and the other vendors. "The guidelines committee will look at fine-tuning for different vendors on how many probes you need to make a certain call, because it is going to vary by chemistry and probe density and other variables," Hagenkord said.

The CCMC is also interested in designing a database that will enable cytogeneticists using arrays in cancer diagnosis and research to share data and make better-informed calls. "We feel very strongly that we should bring the benefits afforded by this new technology to our patients, but, in the case of cancer, it is different, because cancer genomes are very different from the generic genome," said Li. "We need to accumulate the experience and the data and we need to sure the data will make sense, so that is why [the CCMC] will help us to reach that goal."


Have topics you'd like to see covered in BioArray News? Contact the editor at jpetrone [at] genomeweb [.] com.

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