UNASSIGNED: 66 Background: Topoisomerase I (TOP1) is the target of TOP1 inhibitor chemotherapy. The TOP1 gene, located at 20q12, is frequently gained in @entity14 ( @entity14 ). The present study explores the mechanism, frequency and prognostic impact of TOP1 gene alterations in advanced @entity14 . METHODS: Nine @entity14 cell line metaphase spreads were analyzed with a TOP1 probe in combination with a reference probe covering either the centromeric region of chromosome 20 (CEN20) or chromosome 2 ( @entity40234 ). Tissue sections from 154 stage III @entity14 @entity1 , previously studied with TOP1/CEN20, were analyzed with TOP1/ @entity40234 . Relationships between biomarker status and overall survival (OS), time to recurrence (TTR) in @entity14 and to local recurrence (LR; @entity5 only) were analyzed using multivariate statistics. RESULTS: TOP1 alterations were observed in 4 cell line metaphases. In 3 cases, TOP1 gain involved CEN20, indicating either @entity1017 or 20q. In all cell lines @entity40234 was found to reflect chromosomal ploidy levels and therefore the TOP1/ @entity40234 probe combination was selected to identify TOP1 gene gains (TOP1/ @entity40234 ratio >=  1.5). A total of 151 @entity1 @entity5 sections were analyzed with TOP1/ @entity40234 . Among these, 99 @entity1 (65.6%) had TOP1 gain of which 15 @entity1 (10 %) harbored TOP1 amplification (TOP1/CEN20 ratio >=  2.0). For OS, TOP1 amplification showed a trend towards longer OS and TTR (HR: 0.59; 95% CI: 0.31-1.14; p = 0.11; HR: 0.50; 95% CI: 0.23-1.09; p = 0.08; respectively), whereas TOP1 gain did not. For LR in @entity5 @entity1 (n=70), TOP1 gains were significantly associated with shorter time to LR (HR: 1.98, 95% CI: 1.02-3.84; p = 0.04), whereas TOP1 amplifications showed a trend towards longer time to LR (HR: 0.40; 95% CI: 0.14-1.11; p = 0.08). CONCLUSIONS: TOP1 gene gain occurs frequently in stage III @entity14 in a mechanism that often includes CEN20. Using @entity40234 as a measurement for @entity5 ploidy levels, we were able to discriminate between gains and amplifications. TOP1 amplifications showed a trend towards longer OS, TTR and time to LR, whereas TOP1 gains were associated with shorter time to LR. Future studies will investigate the difference between TOP1 gains and amplifications in a larger TOP1 inhibitor treated @entity1 population.

An explorative analysis of TOP1 copy number alterations in a chemonaive stage III XXXX @entity1 cohort.

@entity1 :: ('9606', 'Species') :: ['patients', 'patient'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumor', 'rectal cancer'] @entity40234 :: ('1069', 'Gene') :: ['CEN2'] @entity1017 :: ('MESH:D015430', 'Disease') :: ['gain of chromosome 20'] @entity14 :: ('MESH:D015179', 'Disease') :: ['CRC', 'colorectal cancer']
@entity14 :: (MESH:D015179,Disease) :: ['CRC']
