Bruun, J., Kolberg, M., Ahlquist, T. C., Royrvik, E. C., Nome, T. , Leithe, E., Lind, G. E., Merok, M. A., Rognum, T. O., Bjørkøy, G., Johansen, T., Lindblom, A., Sun, X. F., Svindland, A., Liestøl, K., Nesbakken, A., Skotheim, R. I. and Lothe, R. A. (2015) Regulator of chromosome condensation 2 identifies high-risk patients within both major phenotypes of colorectal cancer. Clinical Cancer Research, 21 (16). pp. 3759-3770. doi:10.1158/1078-0432.CCR-14-3294 ISSN 1078-0432.

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Abstract

PURPOSE:
Colorectal cancer has high incidence and mortality worldwide. Patients with microsatellite instable (MSI) tumors have significantly better prognosis than patients with microsatellite stable (MSS) tumors. Considerable variation in disease outcome remains a challenge within each subgroup, and our purpose was to identify biomarkers that improve prediction of colorectal cancer prognosis.
EXPERIMENTAL DESIGN:
Mutation analyses of 42 MSI target genes were performed in two independent MSI tumor series (n = 209). Markers that were significantly associated with prognosis in the test series were assessed in the validation series, followed by functional and genetic explorations. The clinical potential was further investigated by immunohistochemistry in a population-based colorectal cancer series (n = 903).
RESULTS:
We identified the cell-cycle gene regulator of chromosome condensation 2 (RCC2) as a cancer biomarker. We found a mutation in the 5' UTR region of RCC2 that in univariate and multivariate analyses was significantly associated with improved outcome in the MSI group. This mutation caused reduction of protein expression in dual luciferase gene reporter assays. siRNA knockdown in MSI colon cancer cells (HCT15) caused reduced cell proliferation, cell-cycle arrest, and increased apoptosis. Massive parallel sequencing revealed few RCC2 mutations in MSS tumors. However, weak RCC2 protein expression was significantly associated with poor prognosis, independent of clinical high-risk parameters, and stratifies clinically important patient subgroups with MSS tumors, including elderly patients (>75 years), stage II patients, and those with rectal cancer.
CONCLUSIONS:
Impaired RCC2 affects functional and clinical endpoints of colorectal cancer. High-risk patients with either MSI or MSS tumors can be identified with cost-effective routine RCC2 assays. Clin Cancer Res; 1-12.

Item Type:	Journal Article
Subjects:	Q Science > QC Physics
Divisions:	Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Cell & Developmental Biology Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Colon (Anatomy) -- Cancer -- Tumors -- Diagnosis, Microsatellites (Genetics) , Biochemical markers
Journal or Publication Title:	Clinical Cancer Research
Publisher:	American Association for Cancer Research
ISSN:	1078-0432
Official Date:	15 August 2015
Dates:	Date Event 15 August 2015 Published 24 April 2015 Available 29 March 2015 Accepted 19 December 2014 Submitted
Volume:	21
Number:	16
Number of Pages:	34
Page Range:	pp. 3759-3770
DOI:	10.1158/1078-0432.CCR-14-3294
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access (Creative Commons)
Funder:	Norske kreftforening‏ [Norwegian Cancer Society]
Grant number:	PR-2006-0442, PR-2007-0166

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