The 17q12-q21 amplicon: Her2 and topoisomerase-IIalpha and their importance to the biology of solid tumours.
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.
Mano
Max S
MS
Medical Oncology Unit, Jules Bordet Institut, Bd de Waterloo, 125, 1000 Brussels, Belgium. max.mano@gmail.com
Rosa
Daniela D
DD
De Azambuja
Evandro
E
Ismael
Gustavo F V
GF
Durbecq
Virginie
V
D000951:Antigens, Neoplasm / Q000235:genetics*; D002886:Chromosomes, Human, Pair 17; D004250:DNA Topoisomerases, Type II / Q000235:genetics*; D004273:DNA, Neoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005784:Gene Amplification / Q000235:genetics*; D018734:Genes, erbB-2 / Q000235:genetics*; D005819:Genetic Markers; D006801:Humans; D011379:Prognosis
D000951:Antigens, Neoplasm; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D004250:DNA Topoisomerases, Type II