Characterization of topoisomerase IIα gene amplification and deletion in breast cancer

Abstract

Topoisomerase IIalpha (TOP2A) is a key enzyme in DNA replication and a molecular target for many important anticancer drugs. TOP2A is amplified or deleted together with amplification of the closely located ERBB2/HER-2/neu oncogene in breast cancer. We characterized the copy number aberrations of TOP2A and ERBB2 in 136 primary breast tumors by FISH. Among the 70 primary tumors with ERBB2 amplification, amplification of TOP2A was found in 29 (41%); 30 tumors (43%) showed a physical deletion of TOP2A; and the copy number for TOP2A was not altered in 11 tumors with ERBB2 amplification (16%). No TOP2A gene aberrations were identified in 65 primary tumors without ERBB2 amplification. Fiber FISH revealed that simultaneously amplified ERBB2 and TOP2A were not present in the same amplicon, because repetitive tandem repeat-like signals of ERBB2 and TOP2A were in separate DNA fibers. The deletion of TOP2A (seen in the MDA-361 cell line and in 31 primary tumors) was interstitial, spanning less than two megabases of DNA. Mean copy numbers of TOP2A (2.4 +/- 0.6 for TOP2A vs. 4.9 +/- 1.1 for chromosome 17 centromere) suggest that the deletion of TOP2A occurs before polyploidization of the genome. Eight primary tumors with high-level ERBB2 amplification showed a new type of intratumoral heterogeneity; two different cell clones with either high-level amplification or deletion of TOP2A were found adjacent to each other in the same tumor. These results indicate that amplification of the ERBB2 oncogene is followed by complex secondary genetic aberrations, which lead to amplification or deletion of the TOP2A gene in a majority of tumors. Genes Chromosomes Cancer 26:142-150, 1999.

Modification of topoisomerase genes copy number in newly diagnosed childhood acute lymphoblastic leukemia

“…Amplification of the TOP2A genomic region was already reported in other malignancies, such as in roughly 25% of breast cancers, in which the TOP2A gene was always simultaneously co-amplified with the ERBB2 gene, although fiber fluorescent in situ hybridization demonstrated that both genes are localized on two independent amplicons. 49,50 In ALL cells, in the 16 TOP2A amplified cases that were also analyzed for ERBB2 gene status, co-amplification of both genes was similarly observed in 13 cases, but isolated TOP2A gene amplification could also be observed in three cases (data not shown). Further studies with additional genomic markers are now required to delineate more precisely the extent of TOP2A gene amplicon in ALL cells.…”

Genomic analysis of the HER2/TOP2A amplicon in breast cancer and breast cancer cell lines

“…This region encompasses 420 genes, including HER2, PERLD1, PNMT, PPP1R1B, GSDML, PSMD3, STARD3, THRAP4, TCAP, GRB7, THRA and PPARBP, reported to be overexpressed when amplified. 12,[15][16][17][18]21 In the 10 cases with HER2/TOP2A co-amplification, the smallest region of overlap extended from 34 730.32 to 36 547.20 kb, comprising a region of 1816.88 kb and encompassing 450 genes (Figure 2b). Apart from the genes pertaining to the HER2 amplicon and TOP2A, this region included additional genes that are reported to be overexpressed when amplified: cancer susceptibility candidate 3 (CASC3), retinoic acid receptor alpha (RARA), cell division cycle homologue 6 (CDC6), SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily e, member 1 (SMARCE1) and keratin 10 (KRT10).…”

“…Apart from the genes pertaining to the HER2 amplicon and TOP2A, this region included additional genes that are reported to be overexpressed when amplified: cancer susceptibility candidate 3 (CASC3), retinoic acid receptor alpha (RARA), cell division cycle homologue 6 (CDC6), SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily e, member 1 (SMARCE1) and keratin 10 (KRT10). 12,[16][17][18]22,25 Owing to the selection of criteria of samples harbouring HER2/TOP2A co-amplifications, the prevalence of TOP2A gene deletions could not be analysed.…”

“…[2][3][4] It has recently been proposed that the association of breast cancers harbouring HER2 amplification with response to anthracyclines [5][6][7] may be a direct result of the frequent coamplification of TOP2A, [8][9][10] which maps close to the HER2 gene. TOP2A is co-amplified with HER2 in approximately 40-50% of breast cancers, 11,12 and codes for topoisomerase IIa, a key protein involved in resolving topological problems such as DNA supercoiling, encountered during DNA transcription and replication. This enzyme is a known direct molecular target of anthracyclines.…”

Targeting anthracyclines in early breast cancer: new candidate predictive biomarkers emerge

“…As anthracyclines directly target TOP2A among a range of other proteins, this was a potentially more functionally relevant approach. Data linking both TOP2A amplification and deletion to amplification of the HER2 gene (Jarvinen et al, 1999;Jarvinen and Liu, 2003) gave credence to this hypothesis.…”