Quality Control and Laboratory Issues

Microarrays can be used to identify markers that can be validated using traditional diagnostic applications such as immunohistochemistry and adapted for routine clinical use. However, immunohistochemistry is generally nonquantitative, standardization of antibodies can be laborious, and multiplexing is difficult. More sophisticated and high-throughput validation methods are required for translation of microarray findings into clinical tests. An alternative approach would be to use microarrays in the clinical laboratory without the need for translation to another testing platform. This would require either custom arrays for different indications or whole genome analysis of every sample coupled with an analysis of relevant genes. As commercially available, low-cost, technically simple arrays and easy-to-use analytic software become available, routine clinical use of microarrays can be explored. In addition,the resulting data from clinical microarray testing could be used to generate large expression databases that could serve as an increasing database of centralized and standardized references to which new cancer samples could be compared. The routine clinical use of microar-rays, however, has yet to be established. As molecular signatures of disease are identified, clinical testing for specific markers will become essential for the use of tailored therapies for individual patients.

The success of fully exploiting these powerful approaches depends on several factors: development of appropriate specimen handling techniques to assure target integrity; the accurate selection, amplification, and location of probe molecules; accurate reference sequence information; accurate distinction among multiple products of a single gene; precision image scanning; and reproducible and accurate transformation of image files to numerical data. For DNA and protein microarrays to be reliable tools, they must possess probe sequences that hybridize with high sensitivity and specificity, thereby allowing precise detection of their intended targets. Results must be highly reproducible, and quality control and quality assurance methods must be established. Determining the appropriate level of analytical and biological validation needed for each medical application of microarrays and their supporting computer-based bioinformatics systems raises new challenges for scientists in industry, academia, and regulatory agencies.

Measurements of genomic and proteomic alterations may be used to aid in risk assessment of patient subpopulations, to establish more specific diagnoses, to select optimal therapies, and to monitor patients' responses to therapies, for a broad variety of diseases, most notably

Tissue

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Frozen section

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+/- microdissection

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Targeted IHC

validation pane!

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Figure 29-4. Potential future pathology specimen workflow.

cancer. Clinical trials of new drugs and biologics present unique opportunities for concomitant studies of diagnostics, including ones developed using microarray technologies, in a manner that meets both scientific and regulatory needs. Failure to address diagnostic issues when designing studies that promise new therapies can delay the scientific development and regulatory approval of the new diagnostics, impede full characterization of the new diagnostics due to a loss of controlled patient samples, and compromise evaluation of the therapy itself.

Once the strength of the linkage of genomic and pro-teomic measurements to associated biological outcomes is established, microarray testing methods must be available with sufficient sensitivity, specificity, reproducibility, robustness, reliability, accuracy, and precision for clinical use. Regardless of the evolution of these high-throughput techniques, the practice of surgical pathology will change. One possible view of the future workflow for patient samples is shown in Figure 29-4. As the power of microar-rays and proteomics continues to develop, clinicians will increasingly ask for the availability of clinical microarray and proteomic testing of patient samples at the time of diagnosis. The pathologist will have to be actively involved in the implementation of such studies to ensure the integrity of the studies and the resulting clinical tests.

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