Mechanisms of topoisomerase I (TOP1) gene copy number increase in a stage III colorectal cancer patient cohort.

<h4>Background</h4>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 gen...

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Autores principales: David Hersi Smith, Ib Jarle Christensen, Niels Frank Jensen, Bo Markussen, Maria Unni Rømer, Sune Boris Nygård, Sven Müller, Hans Jørgen Nielsen, Nils Brünner, Kirsten Vang Nielsen
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Publicado: Public Library of Science (PLoS) 2013
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spelling oai:doaj.org-article:322a7ecea97547bfa7fddff12c3549c12021-11-18T07:50:26ZMechanisms of topoisomerase I (TOP1) gene copy number increase in a stage III colorectal cancer patient cohort.1932-620310.1371/journal.pone.0060613https://doaj.org/article/322a7ecea97547bfa7fddff12c3549c12013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23577133/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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).<h4>Methods</h4>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.<h4>Results</h4>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).<h4>Conclusions</h4>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.David Hersi SmithIb Jarle ChristensenNiels Frank JensenBo MarkussenMaria Unni RømerSune Boris NygårdSven MüllerHans Jørgen NielsenNils BrünnerKirsten Vang NielsenPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 4, p e60613 (2013)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
David Hersi Smith
Ib Jarle Christensen
Niels Frank Jensen
Bo Markussen
Maria Unni Rømer
Sune Boris Nygård
Sven Müller
Hans Jørgen Nielsen
Nils Brünner
Kirsten Vang Nielsen
Mechanisms of topoisomerase I (TOP1) gene copy number increase in a stage III colorectal cancer patient cohort.
description <h4>Background</h4>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).<h4>Methods</h4>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.<h4>Results</h4>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).<h4>Conclusions</h4>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.
format article
author David Hersi Smith
Ib Jarle Christensen
Niels Frank Jensen
Bo Markussen
Maria Unni Rømer
Sune Boris Nygård
Sven Müller
Hans Jørgen Nielsen
Nils Brünner
Kirsten Vang Nielsen
author_facet David Hersi Smith
Ib Jarle Christensen
Niels Frank Jensen
Bo Markussen
Maria Unni Rømer
Sune Boris Nygård
Sven Müller
Hans Jørgen Nielsen
Nils Brünner
Kirsten Vang Nielsen
author_sort David Hersi Smith
title Mechanisms of topoisomerase I (TOP1) gene copy number increase in a stage III colorectal cancer patient cohort.
title_short Mechanisms of topoisomerase I (TOP1) gene copy number increase in a stage III colorectal cancer patient cohort.
title_full Mechanisms of topoisomerase I (TOP1) gene copy number increase in a stage III colorectal cancer patient cohort.
title_fullStr Mechanisms of topoisomerase I (TOP1) gene copy number increase in a stage III colorectal cancer patient cohort.
title_full_unstemmed Mechanisms of topoisomerase I (TOP1) gene copy number increase in a stage III colorectal cancer patient cohort.
title_sort mechanisms of topoisomerase i (top1) gene copy number increase in a stage iii colorectal cancer patient cohort.
publisher Public Library of Science (PLoS)
publishDate 2013
url https://doaj.org/article/322a7ecea97547bfa7fddff12c3549c1
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