Microarrays for pharmacogenomic and cancer diagnostics
Highly multiplexed analyses of inherited or somatic sequence variation using high density oligonucleotide microarrays have proven to be very powerful platforms for a new generation of clinical diagnostic tools, and are beginning to make their way into the clinical laboratory. The AmpliChip CYP450 test, designed to genotype the polymorphic CYP2D6 and CYP2C19 drug metabolism genes is the first microarray-based test to receive both CE-mark and FDA regulatory approval. From an analytical point of view, this test has demonstrated the ability of microarrays to simultaneously detect dozens of simple and complex point mutations, gene conversion events, complete gene deletion, as well as gene duplication, including determination of which of 11 different CYP2D6 alleles is duplicated. Increasingly, it may prove important to determine the DNA sequence of a gene in it’s entirety. The AmpliChip p53 test resequences over 1200 nucleotides in 10 exons to detect somatic mutations from tumor tissues, using paraffin embedded tissues as a sample material. Compared to conventional DNA sequencing the highly redundant probe tiling approach is able to detect significantly lower abundance of p53 mutations in samples that contain mixtures of normal and tumor tissue, without the need for microdissection. Emerging data from research with bladder, lung and breast cancers reveal that different classes of p53 mutations are associated with different patient prognosis and survival, and in some cases, differential sensitivity to particular chemotherapy regimens. From a clinical and regulatory perspective, analytical and clinical accuracy as well as clinical utility are the benchmarks against which the value of microarray-based test procedures are measured. The ability to deliver ever more complex genetic analyses is in hand, though translation of more such tests is currently limited by the need to perform large clinical trials that demonstrate their utility in the routine practice of medicine.