TY - JOUR

T1 - TOP1 gene copy numbers in colorectal cancer samples and cell lines and their association to in vitro drug sensitivity

AU - Rømer, Maria Unni

AU - Jensen, Niels Frank

AU - Nielsen, Signe Lykke

AU - Müller, Sven

AU - Nielsen, Kirsten Vang

AU - Nielsen, Hans Jørgen

AU - Brünner, Nils

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

KW - Camptothecin

KW - Cell Death

KW - Cell Line, Tumor

KW - Cell Survival

KW - Colorectal Neoplasms

KW - DNA Topoisomerases, Type I

KW - Drug Resistance, Neoplasm

KW - Gene Dosage

KW - Humans

KW - In Situ Hybridization, Fluorescence

KW - Organoplatinum Compounds

KW - Statistics, Nonparametric

U2 - 10.3109/00365521.2011.638393

DO - 10.3109/00365521.2011.638393

M3 - Journal article

C2 - 22171973

VL - 47

SP - 68

EP - 79

JO - Scandinavian Journal of Gastroenterology

JF - Scandinavian Journal of Gastroenterology

SN - 0036-5521

IS - 1

ER -