OBJECTIVE: DNA topoisomerase I is a putative biomarker of irinotecan efficacy with clinical associations previously demonstrated at the protein level. The purpose of the present study was to perform the first clinical investigation of the association between the DNA topoisomerase I gene (TOP1) copy number and objective response following irinotecan treatment in patients with metastatic colorectal cancer. MATERIALS AND METHODS: Formalin-fixed, paraffin-embedded tumor samples from 78 patients, who received irinotecan monotherapy in second line, were included. TOP1 was assessed by fluorescence in situ hybridization using a technically validated dual-probe combination that hybridizes to TOP1, located at 20q12-q13.1, and to the centromere region of chromosome 20 (CEN-20). In univariate logistic regression models, the TOP1 signal count per cell and the TOP1/CEN-20 ratio were associated with objective response, which was evaluated according to RECIST v.1.1. RESULTS: Gain of TOP1 was identified in 52.6% and 37.2% using the following cutoff values: TOP1 signal count per cell ≥3.6 and TOP1/CEN-20 ≥1.5, respectively. A borderline significant association (Odds ratio (OR): 1.62; p = 0.07) between a stepwise increase in the TOP1 signal count and objective response was demonstrated. In relation to the applied cutoff values, nonsignificant associations with objective response were identified for the TOP1 signal count (OR: 2.41; p = 0.23) and for the TOP1/CEN-20 ratio (OR: 2.05; p = 0.30). CONCLUSIONS: Despite limitations of the study the positive associations between TOP1 and objective response suggest that further analysis in larger tumor material, preferably in a randomized setting, is highly warranted.
OBJECTIVE: DNA topoisomerase I is a putative biomarker of irinotecan efficacy with clinical associations previously demonstrated at the protein level. The purpose of the present study was to perform the first clinical investigation of the association between the DNA topoisomerase I gene (TOP1) copy number and objective response following irinotecan treatment in patients with metastatic colorectal cancer. MATERIALS AND METHODS:Formalin-fixed, paraffin-embedded tumor samples from 78 patients, who received irinotecan monotherapy in second line, were included. TOP1 was assessed by fluorescence in situ hybridization using a technically validated dual-probe combination that hybridizes to TOP1, located at 20q12-q13.1, and to the centromere region of chromosome 20 (CEN-20). In univariate logistic regression models, the TOP1 signal count per cell and the TOP1/CEN-20 ratio were associated with objective response, which was evaluated according to RECIST v.1.1. RESULTS: Gain of TOP1 was identified in 52.6% and 37.2% using the following cutoff values: TOP1 signal count per cell ≥3.6 and TOP1/CEN-20 ≥1.5, respectively. A borderline significant association (Odds ratio (OR): 1.62; p = 0.07) between a stepwise increase in the TOP1 signal count and objective response was demonstrated. In relation to the applied cutoff values, nonsignificant associations with objective response were identified for the TOP1 signal count (OR: 2.41; p = 0.23) and for the TOP1/CEN-20 ratio (OR: 2.05; p = 0.30). CONCLUSIONS: Despite limitations of the study the positive associations between TOP1 and objective response suggest that further analysis in larger tumor material, preferably in a randomized setting, is highly warranted.
Authors: Ida Marie Heeholm Sønderstrup; Sune Boris Nygård; Tim Svenstrup Poulsen; Dorte Linnemann; Jan Stenvang; Hans Jørgen Nielsen; Jiri Bartek; Nils Brünner; Peter Nørgaard; Lene Riis Journal: Mol Oncol Date: 2015-03-04 Impact factor: 6.603
Authors: Pooneh Mokarram; Mohammed Albokashy; Maryam Zarghooni; Mohammad Amin Moosavi; Zahra Sepehri; Qi Min Chen; Andrzej Hudecki; Aliyeh Sargazi; Javad Alizadeh; Adel Rezaei Moghadam; Mohammad Hashemi; Hesam Movassagh; Thomas Klonisch; Ali Akbar Owji; Marek J Łos; Saeid Ghavami Journal: Autophagy Date: 2017-02-23 Impact factor: 16.016
Authors: Iben Kümler; Eva Balslev; Jan Stenvang; Nils Brünner; Bent Ejlertsen; Erik Hugger Jakobsen; Dorte Lisbet Nielsen Journal: BMC Cancer Date: 2019-06-13 Impact factor: 4.430