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Background  Topoisomerase I (Top1) is the target of Top1 inhibitor chemotherapy. The  TOP1  gene, located at 20q12-q13.1, is frequently detected at elevated copy numbers in colorectal cancer (CRC). The present study explores the mechanism, frequency and prognostic impact of  TOP1  gene aberrations in stage III CRC and how these can be detected by fluorescent in situ hybridization (FISH).    Methods  Nine CRC cell line metaphase spreads were analyzed by FISH with a  TOP1  probe in combination with a reference probe covering either the centromeric region of chromosome 20 (CEN-20) or chromosome 2 (CEN-2). Tissue sections from 154 chemonaive stage III CRC patients, previously studied with  TOP1/ CEN-20, were analyzed with  TOP1/ CEN-2. Relationships between biomarker status and overall survival (OS), time to recurrence (TTR) in CRC and time to local recurrence (LR; rectal cancer only) were determined.    Results    TOP1  aberrations were observed in four cell line metaphases. In all cell lines CEN-2 was found to reflect chromosomal ploidy levels and therefore the  TOP1 /CEN-2 probe combination was selected to identify  TOP1  gene gains  (TOP1/ CEN-2≥1.5). One hundred and three patients (68.2%) had  TOP1  gain, of which 15 patients (14.6%) harbored an amplification ( TOP1/ CEN-20≥2.0).  TOP1  gene gain did not have any association with clinical endpoints, whereas  TOP1  amplification showed a non-significant trend towards longer TTR (multivariate HR: 0.50, p = 0.08). Once amplified cases were segregated from other cases of gene gain, non-amplified gene increases ( TOP1 /CEN-2≥1.5 and TOP1/CEN-20<2.0) showed a trend towards shorter TTR (univariate HR: 1.57, p = 0.07).    Conclusions    TOP1  gene copy number increase occurs frequently in stage III CRC in a mechanism that often includes CEN-20. Using CEN-2 as a measurement for tumor ploidy levels, we were able to discriminate between different mechanisms of gene gain, which appeared to differ in prognostic impact.  TOP1  FISH guidelines have been updated.

Mechanisms of Topoisomerase I (TOP1) Gene Copy Number Increase in a Stage III Colorectal Cancer Patient Cohort