title: Topoisomerase-1 gene copy aberrations are frequent in patients with breast cancer.
abstract: Topoisomerase-1 (Top1) targeting drugs have shown promising efficacy in patients with metastatic breast cancer (BC). However, these drugs are rather toxic calling for development and validation of predictive biomarkers to increase the therapeutic index. As these drugs are targeting the Top1 protein and since no validated anti-Top1 antibodies for immunohistochemistry have been reported, we raised the hypothesis that TOP1 gene amplifications may serve as a proxy for the Top1 protein and thereby a biomarker of response to treatment with Top1 inhibitors in BC. The aim was to determine the prevalence of TOP1 gene copy gain in BC. The prevalence of TOP1 gene copy gain was investigated by fluorescence in situ hybridization with a TOP1/CEN-20 probemix in normal breast tissue (N = 100) and in tissue from patients with metastatic BC in a discovery (N = 100) and a validation cohort (N = 205). As amplification of 20q including CEN-20 is common in BC a TOP1/CEN-2 probemix was applied to the validation cohort. More than 30% of the patients had gene copy numbers of ≥ 4 and ∼20% of the patients had TOP1/CEN-20 ratios ≥ 1.5. The CEN-2 probe did not add any information. Gain of the TOP1 gene appears to be common in BC making the gene a potential biomarker for response to treatment with Top1 inhibitors. As 20q amplification is a common finding in BC and as no other suitable reference gene has yet been identified, TOP1 copy number may be a more valid method of detecting gain than using a gene/centromere ratio.
authors: Department of Oncology, Herlev Hospital, University of Copenhagen, Herlev, Denmark.
authors: Iben
authors: I
authors: Kümler
authors: Department of Pathology, Herlev Hospital, University of Copenhagen, Herlev, Denmark.
authors: Eva
authors: E
authors: Balslev
authors: Department of Pathology, Herlev Hospital, University of Copenhagen, Herlev, Denmark.
authors: Tim S
authors: TS
authors: Poulsen
authors: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors: Signe Lykke
authors: SL
authors: Nielsen
authors: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors: Sune Boris
authors: SB
authors: Nygård
authors: Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, University of Copenhagen, Glostrup, Denmark.
authors: Maria Unni
authors: MU
authors: Rømer
authors: The Finsen Laboratory, Rigshospitalet and Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Denmark.
authors: Ib Jarle
authors: IJ
authors: Christensen
authors: Department of Pathology, Herlev Hospital, University of Copenhagen, Herlev, Denmark.
authors: Estrid
authors: E
authors: Høgdall
authors: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors: José
authors: J
authors: Moreira
authors: Department of Oncology, Herlev Hospital, University of Copenhagen, Herlev, Denmark.
authors: Dorte L
authors: DL
authors: Nielsen
authors: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors: Nils
authors: N
authors: Brünner
authors: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors: Jan
authors: J
authors: Stenvang
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D002503:Centromere / Q000235:genetics; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics*; D015331:Cohort Studies; D004264:DNA Topoisomerases, Type I / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D009362:Neoplasm Metastasis
chemical_list: D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human
keywords: breast cancer; fluorescence in situ hybridization; irinotecan; topoisomerase 1 gene