Open Access Research article

An explorative analysis of ERCC1-19q13 copy number aberrations in a chemonaive stage III colorectal cancer cohort

David Hersi Smith12*, Ib Jarle Christensen3, Niels Frank Jensen2, Bo Markussen4, Sven Müller1, Hans Jørgen Nielsen56, Nils Brünner2 and Kirsten Vang Nielsen17

Author Affiliations

1 R&D, Dako A/S, Produktionsvej 42, Glostrup DK-2600, Denmark

2 Section for Molecular Disease Biology, Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Dyrlægevej 88, Frederiksberg DK-1870, Denmark

3 Finsen Laboratory, Rigshospitalet and Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen Biocenter, Ole Maaloevs Vej 5, building 3, 3rd floor, Copenhagen N DK-2200, Denmark

4 Laboratory of Applied Statistics, Department of Mathematical Sciences, Faculty of Science, University of Copenhagen, Universitetsparken 5, Copenhagen Ø DK-2100, Denmark

5 Department of Surgical Gastroenterology 360, Hvidovre Hospital, Kettegård Allé 30, Hvidovre DK-2650, Denmark

6 Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, Copenhagen N DK-2200, Denmark

7 Current address: Centre for Innovation and Research, Ole Maaloevs Vej 3, Copenhagen N DK-2200, Denmark

For all author emails, please log on.

BMC Cancer 2013, 13:489  doi:10.1186/1471-2407-13-489

Published: 21 October 2013

Abstract

Background

Platinum-based chemotherapy has long been used in the treatment of a variety of cancers and functions by inducing DNA damage. ERCC1 and ERCC4 are involved in the removal of this damage and have previously been implicated in resistance to platinum compounds. The aim of the current investigation is to determine the presence, frequency and prognostic impact of ERCC1 or ERCC4 gene copy number alterations in colorectal cancer (CRC).

Methods

Fluorescent in situ hybridization probes directed at ERCC1 and ERCC4 with relevant reference probes were constructed. Probes were tested in a CRC cell line panel and in tumor sections from 152 stage III CRC chemonaive patients. Relationships between biomarker status and clinical endpoints (overall survival, time to recurrence, and local recurrence in rectal cancer) were analyzed by survival statistics.

Results

ERCC1-19q13 copy number alterations were observed in a single cell line metaphase (HT29). In patient material, ERCC1-19q13 copy number gains (ERCC1-19q13/CEN-2 ≥ 1.5) were detected in 27.0% of specimens, whereas ERCC1-19q13 deletions (ERCC1-19q13/CEN-2 < 0.8) were only detected in 1.3%. ERCC1-19q13 gain was significantly associated with longer survival (multivariate analysis, HR: 0.45, 95% CI: 0.20-1.00, p = 0.049) in patients with colon tumors, but not rectal tumors. No ERCC4 aberrations were detected and scoring was discontinued after 50 patients.

Conclusions

ERCC1-19q13 copy number gains occur frequently in stage III CRC and influences survival in patients with colon tumors. Future studies will investigate the effect of ERCC1-19q13 aberrations in a platinum-treated patient population with the aim of developing a predictive biomarker profile for oxaliplatin sensitivity in CRC.

Keywords:
ERCC1; ERCC4; XPF; Colorectal cancer; FISH; Prognosis