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Regulator of Chromosome Condensation 2 Identifies High-Risk Patients within Both Major Phenotypes of Colorectal Cancer
Open accessPublished version of a preprint
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; 21(16); 3759–70. ©2015 AACR.
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Global quantification of mammalian gene expression control
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Metadata
- Authors
- Bruun, J., Kolberg, M., Ahlquist, T. C., Røyrvik, 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., & Lothe, R. A.
- Affiliations
- Oslo University Hospital (NO)
- Norwegian Institute of Public Health (NO)
- 9University College of Sør-Trøndelag, Trondheim, Norway.
- UiT The Arctic University of Norway (NO)
- Karolinska Institutet (SE)
- Linköping University (SE)
- University of Oslo (NO)
- Corresponding author
- Lothe, Ragnhild A.
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2015-08-13
- Volume
- 21
- Issue
- 16
- Pages
- 3759-3770
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2119853462
- Cited by
- 41
- References
- 2
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 1 · 2022: 3 · 2021: 5 · 2020: 7 · 2019: 4 · 2018: 7 · 2017: 4 · 2016: 2
- FWCI
- 3.43
- Type
- journal article
- Language
- en
- Open access
- green
- urn.kb.se
- Licence
- other-oa
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- DiVA (Linkoping University) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
- Keywords
- RCC2, colorectal cancer, microsatellite instability, microsatellite stable tumors, prognostic factors, cell cycle regulation, apoptosis, cell proliferation, rectal cancer, high-risk patient stratification
- MeSH terms
- Age Factors, Aged, Aged, 80 and over, Chromosomal Proteins, Non-Histone, Chromosomes, DNA Mutational Analysis, Female, Humans, Male, Middle Aged, Neoplasm Staging, Prognosis, Biomarkers, Tumor, Colorectal Neoplasms, Disease-Free Survival, Guanine Nucleotide Exchange Factors, Cell Line, Tumor, Microsatellite Instability
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