6th ESACP Congress, Heidelberg, April 7-11, 1999

A002
MEASUREMENT OF DNA SEQUENCE COPY NUMBER VARIATION IN HUMAN DISEASE USING COMPARATIVE GENOMIC HYBRIDIZATION TO MICROARRAYS
Albertson DG 1, Segraves R 1, Zhang XX 1,2, Palmer J 1, Blackwood S 1, Hamilton G 1, Dairkee S 3, Ljung B 1, Bolund L 4, Yuang H 4, Niebuhr E 2, Gray JW 1, Pinkel D 1

1 University of California, San Francisco, San Francisco CA, 2 Medical Genetics, University of Copenhagen, Denmark, 3 Geraldine Brush Cancer Research Institute, San Francisco CA, 4 Inst. of Human Genetics, Aarhus University, Aarhus, Denmark

Comparative genomic hybridization (CGH) has proven to be an effective method for detecting and mapping genetic alterations that are due to changes in DNA sequence copy number. The use of metaphase chromosomes as the hybridization target has previously limited the resolution of CGH to 10-20 Mb. However, we have now implemented a new form of high resolution CGH by replacing the normal metaphase spread with an array of genomic cosmid, P1, and BAC clones. This approach provides a resolution at least a factor of 100 better than standard CGH, as it is determined only by the size and spacing of the target genomic clones. We have applied array CGH to measure variation in DNA sequence copy number occurring in breast cancer and to map the extent of deletions on chromosome 5p in Cri du Chat patients. In addition, the unprecedented high dynamic range and quantitative accuracy of array CGH provide for the first time, the capability to very precisely map copy number profiles across an amplified region for which contiguous and overlapping clones are available as the array target elements. In some tumors, copy number profiles show narrow peaks of amplification. This information focuses attention on the genes mapping to the peak region and may aid in the identification of the candidate driver oncogenes. These initial studies using array CGH illustrate the capability of this technology for scanning the entire genome for copy number aberrations, identifying disease genes and providing diagnostic information.