Background and aims: A positive relationship between topoisomerase-1 (TOP1) protein and sensitivity towards the TOP1 inhibitor irinotecan has been reported in patients with metastatic colorectal cancer (mCRC). The aim of this study was to analyse TOP1 gene copy number variation in tumor tissue from CRC patients and CRC cell lines with different sensitivities to the TOP1 inhibitor SN-38 and oxaliplatin.
Methods: A TOP1 gene probe with a chromosome 20 centromere (CEN-20) reference probe was tested on tumor tissue from 50 stage III CRC patients. Additionally, associations between TOP1/CEN-20 ratio and in vitro sensitivity to SN-38 (the active metabolite of irinotecan) and oxaliplatin were tested for 10 CRC cell lines.
Results: The crude TOP1 copy numbers as well as the TOP1/CEN-20 mean ratio +/- 3 STD were determined in non-affected mucosa and in the malignant epithelium of the tumors. In the malignant epithelium 84% of the samples demonstrated an increased TOP1 gene copy number and 66% had an increased TOP1/CEN-20 ratio compared to the non-affected mucosa. Sixteen (32%) of the tumors had a ratio = 1.5 and 9 of these had a ratio of = 2.0. A positive association was observed between the TOP1 gene copy number and the TOP1/CEN-20 ratio and in vitro sensitivity towards SN-38 but not towards oxaliplatin.
Conclusion: A large fraction of the samples demonstrated an increased TOP1 gene copy number and an increased TOP1/CEN-20 ratio as compared to the non-affected mucosa. The cell line study suggested an association between TOP1 gene copy number or TOP1/CEN-20 ratio and sensitivity to irinotecan but not oxaliplatin.