Gene copy mapping of the ERBB2/TOP2A region in breast cancer

Kris K Jacobson, Larry E Morrison, Benita T Henderson, Beth A Blondin, Kimberly A Wilber, Mona S Legator, Anna O'Hare, Susan C Van Stedum, John H Proffitt, Steve A Seelig, John S Coon
Genes, Chromosomes & Cancer 2004, 40 (1): 19-31
ERBB2 is one of the most important oncogenes in breast cancer, and its disordered expression is commonly associated with gene amplification. Amplification of at least one gene near ERBB2, topoisomerase IIalpha (TOP2A), has been shown to be clinically significant, but the prevailing patterns of gene amplification in this region of chromosome arm 17q have not been studied systematically in clinical cases of breast cancer. For characterizing this region, a commercial ERBB2-containing contig probe and 7 probes prepared from single overlapping BAC and P1 clones lying telomeric to ERBB2 and including TOP2A were hybridized to 77 ERBB2-amplified archival breast tumor specimens from 75 patients. The 7 single-clone probes covered a region of approximately 650 kb starting 114 kb telomeric to ERBB2. Amplification of the ERBB2 contig target alone was found in 32% of the tumors, whereas all 8 probe targets were amplified in 12% of the tumors, based on an amplification criterion of there being more than or equal to 2 targets per chromosome 17 centromere. When one of the 7 overlapping probes encompassing TOP2A indicated amplification within a specimen, all probes telomeric to that probe usually showed amplification. Only 5 specimens had regions of normal or deleted targets separating 2 amplified targets. Also, tumors that showed deletion of TOP2A usually showed deletion of one or more contiguous targets. The observed patterns of amplification and deletion are consistent with the break-fusion-bridge model for gene amplification. TOP2A was amplified in 25% of all tumor specimens and was deleted in 24%, based on a deletion criterion of there being fewer than or equal to 0.75 targets per chromosome 17 centromere. Considering the relevance of the TOP2A gene product to anthracycline therapy and the wealth of other cancer-associated genes within the ERBB2/TOP2A region, the pattern of amplification and deletion near ERBB2 and TOP2A may have a dramatic effect on the malignant potential of breast carcinomas and their response to therapy.

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