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Clin Cancer Res. 2015 Aug 15;21(16):3759-70. doi: 10.1158/1078-0432.CCR-14-3294. Epub 2015 Apr 24.

Regulator of Chromosome Condensation 2 Identifies High-Risk Patients within Both Major Phenotypes of Colorectal Cancer.

Author information

1
Department for Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway. Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
2
Department for Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway.
3
Department for Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. Department of Molecular Biosciences, University of Oslo, Oslo, Norway. Department of Oncology, University of Oxford, ORCRB, Headington, Oxford, United Kingdom.
4
Department for Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
5
Department for Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway. Department of Gastrointestinal Surgery, Aker Hospital-Oslo University Hospital, Oslo, Norway.
6
Faculty of Medicine, University of Oslo, Norway. Division of Forensic Medicine, Department of Forensic Pathology and Clinical Forensic Medicine, the Norwegian Institute of Public Health, Oslo, Norway.
7
University College of Sør-Trøndelag, Trondheim, Norway.
8
Molecular Cancer Research Group, Institute of Medical Biology, University of Tromsø, Tromsø, Norway.
9
Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
10
Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, County Council of Östergötland, University of Linköping, Linköping, Sweden.
11
Faculty of Medicine, University of Oslo, Norway. Department of Pathology, Oslo University Hospital, Oslo, Norway.
12
Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway. Department of Informatics, Faculty of Mathematics and Natural Sciences, Oslo, Norway.
13
K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway. Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway. Department of Gastrointestinal Surgery, Aker Hospital-Oslo University Hospital, Oslo, Norway. Faculty of Medicine, University of Oslo, Norway.
14
Department for Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway. Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway. Department of Informatics, Faculty of Mathematics and Natural Sciences, Oslo, Norway.
15
Department for Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway. Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway. Department of Molecular Biosciences, University of Oslo, Oslo, Norway. Ragnhild.A.Lothe@rr-research.no.

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.

PMID:
25910952
DOI:
10.1158/1078-0432.CCR-14-3294
[Indexed for MEDLINE]
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