The 17q12-q21 amplicon: Her2 and topoisomerase-II alpha 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: 6.47). 03/2007; 33(1):64-77. DOI: 10.1016/j.ctrv.2006.10.001
Source: PubMed

ABSTRACT 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.

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    • "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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    British Journal of Cancer 12/2009; 102(2):361-8. DOI:10.1038/sj.bjc.6605478 · 4.82 Impact Factor
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    • "It also indicates the importance of being able to refine this complex dataset down to a single credible target recognisable as significant. Given that there are other established routes to ERBB2 overexpression in breast tumours including genomic amplification [Mano et al., 2007], the clinically significant facet of the work is not the mechanism, which is not directly testable in the clinical material, but the correlation. What the field lacks is an association between the site and the proteins in ChIP from clinical material and this is universally true for research that seeks to employ ChIP to shed light on transcriptional networks in cancer. "
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    • "These areas may also contain genes that through gain or loss of function could cooperate to establish the biology of HER2 amplified tumors. The topoisomerase IIa (TOP2A) gene on 17q21 is frequently co-amplified with HER2 and may explain why HER2 overrexpressing breast cancers are particularly sensitive to treatment with topoisomerase inhibitors (Mano et al. 2006). "
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