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Gene copy mapping of the ERBB2/TOP2A region in breast cancer
Kris K Jacobson1, Larry E Morrison, Benita T Henderson
1Vysis, Inc, Downers Grove, IL 60515, USA.
Abstract:
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.
Insights
Gene amplification patterns near ERBB2 and TOP2A in breast cancer were studied. Amplification of TOP2A occurred in 25% of tumors, impacting treatment response.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- ERBB2 (Erb-B2 receptor tyrosine kinase 2) is a key oncogene in breast cancer, often amplified.
- Gene amplification near ERBB2, including TOP2A (topoisomerase II alpha), is clinically significant but not well-characterized.
- Understanding amplification patterns in the 17q region is crucial for breast cancer prognosis and therapy.
Purpose of the Study:
- To systematically characterize gene amplification and deletion patterns in the 17q chromosome region near ERBB2 in breast cancer.
- To investigate the relationship between ERBB2, TOP2A, and other nearby genes in amplified regions.
- To correlate these genomic alterations with potential clinical significance.
Main Methods:
- Hybridization of ERBB2-containing probes and 7 BAC/P1 clone probes (including TOP2A) to 77 ERBB2-amplified breast tumor specimens.
- Analysis of amplification (≥2 targets/chromosome 17 centromere) and deletion (≤0.75 targets/chromosome 17 centromere) patterns.
- Assessment of contiguous gene amplification and deletion based on probe location.
Main Results:
- ERBB2 amplification alone was found in 32% of tumors; all 8 probes amplified in 12%.
- TOP2A was amplified in 25% and deleted in 24% of tumor specimens.
- Amplification and deletion patterns observed are consistent with the break-fusion-bridge model of gene amplification.
Conclusions:
- The patterns of gene amplification and deletion in the ERBB2/TOP2A region significantly influence breast cancer's malignant potential.
- TOP2A alterations and nearby gene copy number variations may impact patient response to anthracycline therapies.
- Further investigation into these genomic alterations is warranted for therapeutic targeting.
