The 17q12-q21 amplicon: Her2 and topoisomerase-IIα and their importance to the biology of solid tumours
Medical Oncology Unit, Jules Bordet Institut, Bd de Waterloo, 125, 1000 Brussels, Belgium. Cancer Treatment Reviews
(Impact Factor: 7.59).
03/2007; 33(1):64-77. DOI: 10.1016/j.ctrv.2006.10.001
Her2 and topoisomerase-IIalpha (T2A) gene amplification are separate events, although the latter is more frequently seen in Her2 amplified (34-90%) than in Her2 non-amplified (5-10%) tumours. There is a better correlation between Her2 amplification and protein overexpression in breast cancer (BC) than in other tumour types. This marker is also considered a powerful prognostic factor in BC, with similar data emerging in other solid tumours such as bladder, ovarian, endometrial, gastro-oesophageal and non-small cell lung cancer. Her2 amplification and/or overexpression are highly predictive of response to HER2-targeted compounds such as trastuzumab and lapatinib but have been inconsistent predictors of response to cytotoxic chemotherapy. There is also evidence that these tumours are relatively resistant to anti-oestrogen therapy (tamoxifen) but not to oestrogen deprivation (e.g. with aromatase inhibitors). T2A aberrations are uncommon events in solid tumours, with an overall prevalence of approximately 10%. T2A amplification has shown inconsistent correlation with T2A protein expression in preclinical and clinical studies, mainly because non-genetic events such as proliferation rate can also affect protein expression. Expression of T2A protein has not been shown to reliably predict response to T2A inhibitors, despite the fact that this enzyme is the direct target for these compounds. In BC, T2A amplification appears to be a good predictor of response to anthracyclines, but these data are still in the process of validation. The significance of T2A deletions is currently under investigation, but contrary to what was previously thought, it may also predict benefit from treatment with T2A inhibitors. The prognostic significance of T2A aberrations is currently unknown.
Available from: Olivia O'Leary
- "Thus, up-regulated levels of TOP2A protein are found in proliferating cancer cells, and TOP2A is essential for the viability of these dividing cells. Consistent with its role in cell proliferation, genetic aberrations in TOP2A are linked to numerous human cancers . To facilitate proper separation of chromatids and DNA replication, TOP2A generates transient double-stranded breaks in DNA [7-10]. "
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ABSTRACT: Genetic alterations in human topoisomerase II alpha (TOP2A) are linked to cancer susceptibility. TOP2A decatenates chromosomes and thus is necessary for multiple aspects of cell division including DNA replication, chromosome condensation and segregation. Topoisomerase II alpha is also required for embryonic development in mammals, as mouse Top2a knockouts result in embryonic lethality as early as the 4-8 cell stage. The purpose of this study was to determine whether the extended developmental capability of zebrafish top2a mutants arises from maternal expression of top2a or compensation from its top2b paralogue.
Here, we describe bloody minded (blm), a novel mutant of zebrafish top2a. In contrast to mouse Top2a nulls, zebrafish top2a mutants survive to larval stages (4-5 day post fertilization). Developmental analyses demonstrate abundant expression of maternal top2a but not top2b. Inhibition or poisoning of maternal topoisomerase II delays embryonic development by extending the cell cycle M-phase. Zygotic top2a and top2b are co-expressed in the zebrafish CNS, but endogenous or ectopic top2b RNA appear unable to prevent the blm phenotype.
We conclude that maternal top2a enables zebrafish development before the mid-zygotic transition (MZT) and that zebrafish top2a and top2b are not functionally redundant during development after activation of the zygotic genome.
Available from: Frederic Fina
- "Nevertheless, the molecular variations within the Chr17q amplicon and their clinical implications remain largely unknown. Indeed, besides TOP2A, other genes which are located not only in the HER2 smallest region of amplification (SRA) [23,24] but also all along the long arm of the Chr17 [5,24-27] might also be amplified, and they could play functional roles in breast cancer development and progression. To explore this hypothesis, we carried out a quantitative analysis of a set of 11 genes that were chosen for their localization along Chr17q12-q21 and for their putative role in breast cancer development. "
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ABSTRACT: Human epidermal growth factor receptor 2 (HER2)-amplified breast cancers represent a tumor subtype with chromosome 17q rearrangements that lead to frequent gene amplifications. The aim of this study was to quantify the amplification of genes located on chromosome 17q and to analyze the relations between the pattern of gene amplifications and the patients' characteristics and survival.
Patients with HER2-positive breast tumors (HER2 score of 3+ by immunohistochemistry or positive for HER2 amplification by fluorescence in situ hybridization (FISH)) (n = 86) and with HER2-negative breast tumors (n = 40) (negative controls) were included in this study. Using a quantitative polymerase chain reaction method and DNA extracted from frozen tumor specimens, 11 genes (MED1, STARD3, HER2, GRB7, THRA, RARA, TOP2A, IGFBP4, CCR7, KRT20, KRT19 and GAS), which are localized within Chr17q12-q21 and have a putative role in breast cancer development, were quantified. Relapse-free and overall survival rates were estimated from the date of surgery to the date of the event of interest (recurrence or death) using the Kaplan-Meier method.
Gene amplification was observed only in HER2-positive tumors, and the frequency of amplification decreased with the distance of the gene from HER2. HER2 presented the highest level of amplification. TOP2A was not included in the smallest region of amplification involving HER2. Amplification of RARA, KRT20 and KRT19 was significantly associated with node-positive breast cancer (P = 0.030, P = 0.002 and P = 0.033, respectively). During a median follow-up period of 55 months (range, 6 to 81 months), the subgroup of patients with hormone receptor-negative cancer and without TOP2A amplification showed the worst survival (relapse-free survival: hazard ratio (HR) = 0.29, 95% confidence interval (95% CI), 0.13 to 0.65, P = 0.001; and overall survival: HR = 0.28, 95% CI, 0.10 to 0.76, P = 0.008).
HER2 amplification seems to drive genomic instability along chromosome 17q, leading to different patterns of gene amplification. This study confirms the clinical importance of identifying, among patients with HER2-positive breast tumors, the subgroup of patients with hormone receptor-negative and nonamplified TOP2A cancers as they have the worst prognosis.
Available from: Balázs Györffy
- "As it was examined in the last decades, overexpression of individual genes can be associated with resistance against given agents. ABCB1 gene strongly correlates to chemoresistance (Clarke et al 1992; Kamata et al, 2008; Larbcharoensub et al, 2008; Shi et al, 2008), TOP2A is a potential gene for predicting anthracyclin resistance (Molina et al, 2005; Tanner et al, 2006; Harris et al, 2007; Mano et al, 2007). Expression of metallothioneins is linked to tamoxifen resistance (Surowiak et al, 2004), and the gene Tau is a predictor of resistance against neoadjuvant paclitaxel therapy (Rouzier et al, 2005; Andre et al, 2007). "
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ABSTRACT: To date individual markers have failed to correctly predict resistance against anticancer agents in breast cancer. We used gene expression patterns attributable to chemotherapy-resistant cells to detect potential new biomarkers related to anthracycline resistance. One of the genes, PSMB7, was selected for further functional studies and clinical validation.
We contrasted the expression profiles of four pairs of different human tumour cell lines and of their counterparts resistant to doxorubicin. Observed overexpression of PSMB7 in resistant cell lines was validated by immunohistochemistry. To examine its function in chemoresistance, we silenced the gene by RNA interference (RNAi) in doxorubicin-resistant MCF-7 breast cancer cells, then cell vitality was measured after doxorubicin treatment. Microarray gene expression from GEO raw microarray samples with available progression-free survival data was downloaded, and expression of PSMB7 was used for grouping samples.
After doxorubicin treatment, 79.8+/-13.3% of resistant cells survived. Silencing of PSMB7 in resistant cells decreased survival to 31.8+/-6.4% (P>0.001). A similar effect was observed after paclitaxel treatment. In 1592 microarray samples, the patients with high PSMB7 expression had a significantly shorter survival than the patients with low expression (P<0.001).
Our findings suggest that high PSMB7 expression is an unfavourable prognostic marker in breast cancer.
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