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

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 - 2012/1

Y1 - 2012/1

N2 - Objective. A positive relationship between topoisomerase-1 (TOP1) protein and sensitivity toward the TOP1 inhibitor irinotecan has been reported in patients with metastatic colorectal cancer (mCRC). In this study, we analyzed 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. Material and methods. A TOP1 gene probe with a chromosome 20 centromere (CEN-20) reference probe was applied on normal mucosa and on tumor tissue from 50 stage III CRC patients. Additionally, associations between TOP1/CEN-20 ratio and in vitro sensitivity to SN-38 (irinotecan) and oxaliplatin were tested on 10 CRC cell lines. Results. In the malignant epithelium, 84% of the samples demonstrated an increased TOP1 gene copy number and 64% had an increased TOP1/CEN-20 ratio compared with the non-affected mucosa. Sixteen (32%) of the tumors had a ratio of ≥1.5 and 9 (18%) 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 toward SN-38, but not toward oxaliplatin. Conclusions. A large fraction of the clinical samples demonstrated increased TOP1 gene copy number and increased TOP1/CEN-20 ratio. 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 - Objective. A positive relationship between topoisomerase-1 (TOP1) protein and sensitivity toward the TOP1 inhibitor irinotecan has been reported in patients with metastatic colorectal cancer (mCRC). In this study, we analyzed 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. Material and methods. A TOP1 gene probe with a chromosome 20 centromere (CEN-20) reference probe was applied on normal mucosa and on tumor tissue from 50 stage III CRC patients. Additionally, associations between TOP1/CEN-20 ratio and in vitro sensitivity to SN-38 (irinotecan) and oxaliplatin were tested on 10 CRC cell lines. Results. In the malignant epithelium, 84% of the samples demonstrated an increased TOP1 gene copy number and 64% had an increased TOP1/CEN-20 ratio compared with the non-affected mucosa. Sixteen (32%) of the tumors had a ratio of ≥1.5 and 9 (18%) 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 toward SN-38, but not toward oxaliplatin. Conclusions. A large fraction of the clinical samples demonstrated increased TOP1 gene copy number and increased TOP1/CEN-20 ratio. 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

SN - 0036-5521

VL - 47

SP - 68

EP - 79

JO - Scandinavian Journal of Gastroenterology

JF - Scandinavian Journal of Gastroenterology

IS - 1

ER -