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118 results on '"Svindland A"'

1. Decision-Making Frameworks for Network Resilience -- Managing and Mitigating Systemic (Cyber) Risk

Author

Svindland, Gregor and Voß, Alexander

Subjects
Quantitative Finance - Risk Management, Computer Science - Cryptography and Security, Computer Science - Discrete Mathematics, Computer Science - Networking and Internet Architecture, Electrical Engineering and Systems Science - Systems and Control, 05C82, 05C90, 90B18, 91B05, 91G45, 93B70
Abstract

We introduce a decision-making framework tailored for the management of systemic risk in networks. This framework is constructed upon three fundamental components: (1) a set of acceptable network configurations, (2) a set of interventions aimed at risk mitigation, and (3) a cost function quantifying the expenses associated with these interventions. While our discussion primarily revolves around the management of systemic cyber risks in digital networks, we concurrently draw parallels to risk management of other complex systems where analogous approaches may be adequate.

Published
2023

3. Bipolar Theorems for Sets of Non-negative Random Variables

Author

Langner, Johannes and Svindland, Gregor

Subjects
Mathematics - Probability, Mathematics - Functional Analysis, Quantitative Finance - Mathematical Finance, 46A20, 46E30, 46N10, 46N30, 60B11, 91G80
Abstract

This paper assumes a robust, in general not dominated, probabilistic framework and provides necessary and sufficient conditions for a bipolar representation of subsets of the set of all quasi-sure equivalence classes of non-negative random variables, without any further conditions on the underlying measure space. This generalizes and unifies existing bipolar theorems proved under stronger assumptions on the robust framework. Applications are in areas of robust financial modeling.

Published
2022

4. Building Resilience in Cybersecurity -- An Artificial Lab Approach

Author

Awiszus, Kerstin, Bell, Yannick, Lüttringhaus, Jan, Svindland, Gregor, Voß, Alexander, and Weber, Stefan

Subjects
Computer Science - Cryptography and Security, Computer Science - Social and Information Networks, Electrical Engineering and Systems Science - Systems and Control, Mathematics - Probability, Quantitative Finance - Risk Management
Abstract

Based on classical contagion models we introduce an artificial cyber lab: the digital twin of a complex cyber system in which possible cyber resilience measures may be implemented and tested. Using the lab, in numerical case studies, we identify two classes of measures to control systemic cyber risks: security- and topology-based interventions. We discuss the implications of our findings on selected real-world cybersecurity measures currently applied in the insurance and regulation practice or under discussion for future cyber risk control. To this end, we provide a brief overview of the current cybersecurity regulation and emphasize the role of insurance companies as private regulators. Moreover, from an insurance point of view, we provide first attempts to design systemic cyber risk obligations and to measure the systemic risk contribution of individual policyholders.

Published
2022

5. Modeling and Pricing Cyber Insurance -- Idiosyncratic, Systematic, and Systemic Risks

Author

Awiszus, Kerstin, Knispel, Thomas, Penner, Irina, Svindland, Gregor, Voß, Alexander, and Weber, Stefan

Subjects
Quantitative Finance - Risk Management, Mathematics - Probability
Abstract

The paper provides a comprehensive overview of modeling and pricing cyber insurance and includes clear and easily understandable explanations of the underlying mathematical concepts. We distinguish three main types of cyber risks: idiosyncratic, systematic, and systemic cyber risks. While for idiosyncratic and systematic cyber risks, classical actuarial and financial mathematics appear to be well-suited, systemic cyber risks require more sophisticated approaches that capture both network and strategic interactions. In the context of pricing cyber insurance policies, issues of interdependence arise for both systematic and systemic cyber risks; classical actuarial valuation needs to be extended to include more complex methods, such as concepts of risk-neutral valuation and (set-valued) monetary risk measures.

Published
2022

12. Effects of heavy-load strength training during (neo-)adjuvant chemotherapy on muscle strength, muscle fiber size, myonuclei, and satellite cells in women with breast cancer

Author

Vikmoen, Olav, Strandberg, Emelie, Vassbakk Svindland, Karianne, Henriksson, Anna, Mazzoni, Anne-Sophie, Johansson, Birgitta, Jönsson, Janniz, Karakatsanis, Andreas, Annebäck, Matilda, Kudren, David, Lindman, Henrik, Warnberg, Fredrik, Berntsen, Sveinung, Demmelmaier, Ingrid, Nordin, Karin, Raastad, Truls, Vikmoen, Olav, Strandberg, Emelie, Vassbakk Svindland, Karianne, Henriksson, Anna, Mazzoni, Anne-Sophie, Johansson, Birgitta, Jönsson, Janniz, Karakatsanis, Andreas, Annebäck, Matilda, Kudren, David, Lindman, Henrik, Warnberg, Fredrik, Berntsen, Sveinung, Demmelmaier, Ingrid, Nordin, Karin, and Raastad, Truls

Abstract

To investigate the effects of heavy-load strength training during (neo-)adjuvant chemotherapy in women with breast cancer on muscle strength, body composition, muscle fiber size, satellite cells, and myonuclei. Women with stage I-III breast cancer were randomly assigned to a strength training group (ST, n = 23) performing supervised heavy-load strength training twice a week during chemotherapy, or a usual care control group (CON, n = 17). Muscle strength and body composition were measured and biopsies from m. vastus lateralis collected before the first cycle of chemotherapy (T0) and after chemotherapy and training (T1). Muscle strength increased significantly more in ST than in CON in chest-press (ST: +10 +/- 8%, p < .001, CON: -3 +/- 5%, p = .023) and leg-press (ST: +11 +/- 8%, p < .001, CON: +3 +/- 6%, p = .137). Both groups reduced fat-free mass (ST: -4.9 +/- 4.0%, p < .001, CON: -5.2 +/- 4.9%, p = .004), and increased fat mass (ST: +15.3 +/- 16.5%, p < .001, CON: +16.3 +/- 19.8%, p = .015) with no significant differences between groups. No significant changes from T0 to T1 and no significant differences between groups were observed in muscle fiber size. For myonuclei per fiber a non-statistically significant increase in CON and a non-statistically significant decrease in ST in type I fibers tended (p = .053) to be different between groups. Satellite cells tended to decrease in ST (type I: -14 +/- 36%, p = .097, type II: -9 +/- 55%, p = .084), with no changes in CON and no differences between groups. Strength training during chemotherapy improved muscle strength but did not significantly affect body composition, muscle fiber size, numbers of satellite cells, and myonuclei compared to usual care.

Published
2024
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13. Building resilience in cybersecurity: An artificial lab approach.

Author

Awiszus, Kerstin, Bell, Yannick, Lüttringhaus, Jan, Svindland, Gregor, Voß, Alexander, and Weber, Stefan

Subjects
DIGITAL twins, SYSTEMIC risk (Finance), INSURANCE companies, PRIVATE companies, BUSINESS insurance
Abstract

Based on classical contagion models we introduce an artificial cyber lab: the digital twin of a complex cyber system in which possible cyber resilience measures may be implemented and tested. Using the lab, in numerical case studies, we identify two classes of measures to control systemic cyber risks: security‐ and topology‐based interventions. We discuss the implications of our findings on selected real‐world cybersecurity measures currently applied in the insurance and regulation practice or under discussion for future cyber risk control. To this end, we provide a brief overview of the current cybersecurity regulation and emphasize the role of insurance companies as private regulators. Moreover, from an insurance point of view, we provide first attempts to design systemic cyber risk obligations and to measure the systemic risk contribution of individual policyholders. [ABSTRACT FROM AUTHOR]

Published
2024
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17. Supplementary Figure 1 from The β2-Adrenergic Receptor Is a Molecular Switch for Neuroendocrine Transdifferentiation of Prostate Cancer Cells

Author

Braadland, Peder R., primary, Ramberg, Håkon, primary, Grytli, Helene Hartvedt, primary, Urbanucci, Alfonso, primary, Nielsen, Heidi Kristin, primary, Guldvik, Ingrid Jenny, primary, Engedal, Andreas, primary, Ketola, Kirsi, primary, Wang, Wanzhong, primary, Svindland, Aud, primary, Mills, Ian G., primary, Bjartell, Anders, primary, and Taskén, Kristin Austlid, primary

Published
2023
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18. Supplementary Figure 6 from The β2-Adrenergic Receptor Is a Molecular Switch for Neuroendocrine Transdifferentiation of Prostate Cancer Cells

Author

Braadland, Peder R., primary, Ramberg, Håkon, primary, Grytli, Helene Hartvedt, primary, Urbanucci, Alfonso, primary, Nielsen, Heidi Kristin, primary, Guldvik, Ingrid Jenny, primary, Engedal, Andreas, primary, Ketola, Kirsi, primary, Wang, Wanzhong, primary, Svindland, Aud, primary, Mills, Ian G., primary, Bjartell, Anders, primary, and Taskén, Kristin Austlid, primary

Published
2023
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19. Supplementary Data from The β2-Adrenergic Receptor Is a Molecular Switch for Neuroendocrine Transdifferentiation of Prostate Cancer Cells

Author

Braadland, Peder R., primary, Ramberg, Håkon, primary, Grytli, Helene Hartvedt, primary, Urbanucci, Alfonso, primary, Nielsen, Heidi Kristin, primary, Guldvik, Ingrid Jenny, primary, Engedal, Andreas, primary, Ketola, Kirsi, primary, Wang, Wanzhong, primary, Svindland, Aud, primary, Mills, Ian G., primary, Bjartell, Anders, primary, and Taskén, Kristin Austlid, primary

Published
2023
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20. Supplementary Figure 7 from The β2-Adrenergic Receptor Is a Molecular Switch for Neuroendocrine Transdifferentiation of Prostate Cancer Cells

Author

Braadland, Peder R., primary, Ramberg, Håkon, primary, Grytli, Helene Hartvedt, primary, Urbanucci, Alfonso, primary, Nielsen, Heidi Kristin, primary, Guldvik, Ingrid Jenny, primary, Engedal, Andreas, primary, Ketola, Kirsi, primary, Wang, Wanzhong, primary, Svindland, Aud, primary, Mills, Ian G., primary, Bjartell, Anders, primary, and Taskén, Kristin Austlid, primary

Published
2023
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21. Supplementary Figure 5 from The β2-Adrenergic Receptor Is a Molecular Switch for Neuroendocrine Transdifferentiation of Prostate Cancer Cells

Author

Braadland, Peder R., primary, Ramberg, Håkon, primary, Grytli, Helene Hartvedt, primary, Urbanucci, Alfonso, primary, Nielsen, Heidi Kristin, primary, Guldvik, Ingrid Jenny, primary, Engedal, Andreas, primary, Ketola, Kirsi, primary, Wang, Wanzhong, primary, Svindland, Aud, primary, Mills, Ian G., primary, Bjartell, Anders, primary, and Taskén, Kristin Austlid, primary

Published
2023
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22. Data from The β2-Adrenergic Receptor Is a Molecular Switch for Neuroendocrine Transdifferentiation of Prostate Cancer Cells

Author

Braadland, Peder R., primary, Ramberg, Håkon, primary, Grytli, Helene Hartvedt, primary, Urbanucci, Alfonso, primary, Nielsen, Heidi Kristin, primary, Guldvik, Ingrid Jenny, primary, Engedal, Andreas, primary, Ketola, Kirsi, primary, Wang, Wanzhong, primary, Svindland, Aud, primary, Mills, Ian G., primary, Bjartell, Anders, primary, and Taskén, Kristin Austlid, primary

Published
2023
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23. Supplementary Figure 2 from The β2-Adrenergic Receptor Is a Molecular Switch for Neuroendocrine Transdifferentiation of Prostate Cancer Cells

Author

Braadland, Peder R., primary, Ramberg, Håkon, primary, Grytli, Helene Hartvedt, primary, Urbanucci, Alfonso, primary, Nielsen, Heidi Kristin, primary, Guldvik, Ingrid Jenny, primary, Engedal, Andreas, primary, Ketola, Kirsi, primary, Wang, Wanzhong, primary, Svindland, Aud, primary, Mills, Ian G., primary, Bjartell, Anders, primary, and Taskén, Kristin Austlid, primary

Published
2023
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24. Supplementary Figure 4 from The β2-Adrenergic Receptor Is a Molecular Switch for Neuroendocrine Transdifferentiation of Prostate Cancer Cells

Author

Braadland, Peder R., primary, Ramberg, Håkon, primary, Grytli, Helene Hartvedt, primary, Urbanucci, Alfonso, primary, Nielsen, Heidi Kristin, primary, Guldvik, Ingrid Jenny, primary, Engedal, Andreas, primary, Ketola, Kirsi, primary, Wang, Wanzhong, primary, Svindland, Aud, primary, Mills, Ian G., primary, Bjartell, Anders, primary, and Taskén, Kristin Austlid, primary

Published
2023
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25. Supplementary Figure 8 from The β2-Adrenergic Receptor Is a Molecular Switch for Neuroendocrine Transdifferentiation of Prostate Cancer Cells

Author

Braadland, Peder R., primary, Ramberg, Håkon, primary, Grytli, Helene Hartvedt, primary, Urbanucci, Alfonso, primary, Nielsen, Heidi Kristin, primary, Guldvik, Ingrid Jenny, primary, Engedal, Andreas, primary, Ketola, Kirsi, primary, Wang, Wanzhong, primary, Svindland, Aud, primary, Mills, Ian G., primary, Bjartell, Anders, primary, and Taskén, Kristin Austlid, primary

Published
2023
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26. Supplementary Figure 3 from The β2-Adrenergic Receptor Is a Molecular Switch for Neuroendocrine Transdifferentiation of Prostate Cancer Cells

Author

Braadland, Peder R., primary, Ramberg, Håkon, primary, Grytli, Helene Hartvedt, primary, Urbanucci, Alfonso, primary, Nielsen, Heidi Kristin, primary, Guldvik, Ingrid Jenny, primary, Engedal, Andreas, primary, Ketola, Kirsi, primary, Wang, Wanzhong, primary, Svindland, Aud, primary, Mills, Ian G., primary, Bjartell, Anders, primary, and Taskén, Kristin Austlid, primary

Published
2023
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27. Building resilience in cybersecurity: An artificial lab approach

Author

Awiszus, Kerstin, Bell, Yannick, Lüttringhaus, Jan, Svindland, Gregor, Voß, Alexander, Weber, Stefan, Awiszus, Kerstin, Bell, Yannick, Lüttringhaus, Jan, Svindland, Gregor, Voß, Alexander, and Weber, Stefan

Abstract

Based on classical contagion models we introduce an artificial cyber lab: the digital twin of a complex cyber system in which possible cyber resilience measures may be implemented and tested. Using the lab, in numerical case studies, we identify two classes of measures to control systemic cyber risks: security- and topology-based interventions. We discuss the implications of our findings on selected real-world cybersecurity measures currently applied in the insurance and regulation practice or under discussion for future cyber risk control. To this end, we provide a brief overview of the current cybersecurity regulation and emphasize the role of insurance companies as private regulators. Moreover, from an insurance point of view, we provide first attempts to design systemic cyber risk obligations and to measure the systemic risk contribution of individual policyholders.

Published
2023

28. Measures of Resilience to Cyber Contagion -- An Axiomatic Approach for Complex Systems

Author

Svindland, Gregor, Voß, Alexander, Svindland, Gregor, and Voß, Alexander

Abstract

We introduce a novel class of risk measures designed for the management of systemic risk in networks. In contrast to prevailing approaches, these risk measures target the topological configuration of the network in order to mitigate the propagation risk of contagious threats. While our discussion primarily revolves around the management of systemic cyber risks in digital networks, we concurrently draw parallels to risk management of other complex systems where analogous approaches may be adequate.

Published
2023

31. Supplementary Figure 2 from The β2-Adrenergic Receptor Is a Molecular Switch for Neuroendocrine Transdifferentiation of Prostate Cancer Cells

Author

Kristin Austlid Taskén, Anders Bjartell, Ian G. Mills, Aud Svindland, Wanzhong Wang, Kirsi Ketola, Andreas Engedal, Ingrid Jenny Guldvik, Heidi Kristin Nielsen, Alfonso Urbanucci, Helene Hartvedt Grytli, Håkon Ramberg, and Peder R. Braadland

Abstract

NEtD characterization shADRB2 and shCtrl cell lines

Published
2023
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34. Data from The β2-Adrenergic Receptor Is a Molecular Switch for Neuroendocrine Transdifferentiation of Prostate Cancer Cells

Author

Kristin Austlid Taskén, Anders Bjartell, Ian G. Mills, Aud Svindland, Wanzhong Wang, Kirsi Ketola, Andreas Engedal, Ingrid Jenny Guldvik, Heidi Kristin Nielsen, Alfonso Urbanucci, Helene Hartvedt Grytli, Håkon Ramberg, and Peder R. Braadland

Abstract

The incidence of treatment-related neuroendocrine prostate cancer (t-NEPC) is rising as more potent drugs targeting the androgen signaling axis are clinically implemented. Neuroendocrine transdifferentiation (NEtD), an putative initial step in t-NEPC development, is induced by androgen-deprivation therapy (ADT) or anti-androgens, and by activation of the β2-adrenergic receptor (ADRB2) in prostate cancer cell lines. Thus, understanding whether ADRB2 is involved in ADT-initiated NEtD may assist in developing treatment strategies that can prevent or reverse t-NEPC emergence, thereby prolonging therapeutic responses. Here we found that in primary, treatment-naïve prostate cancers, ADRB2 mRNA was positively correlated with expression of luminal differentiation markers, and ADRB2 protein levels were inversely correlated with Gleason grade. ADRB2 mRNA was upregulated in metastatic prostate cancer, and progressively downregulated during ADT and t-NEPC emergence. In androgen-deprivated medium, high ADRB2 was required for LNCaP cells to undergo NEtD, measured as increased neurite outgrowth and expression of neuron differentiation and neuroendocrine genes. ADRB2 overexpression induced a neuroendocrine-like morphology in both androgen receptor (AR)-positive and -negative prostate cancer cell lines. ADRB2 downregulation in LNCaP cells increased canonical Wnt signaling, and GSK3α/β inhibition reduced the expression of neuron differentiation and neuroendocrine genes. In LNCaP xenografts, more pronounced castration-induced NEtD was observed in tumors derived from high than low ADRB2 cells. In conclusion, high ADRB2 expression is required for ADT-induced NEtD, characterized by ADRB2 downregulation and t-NEPC emergence.Implications:This data suggest a potential application of β-blockers to prevent cancer cells committed to a neuroendocrine lineage from evolving into t-NEPC.

Published
2023
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37. Supplementary Data from The β2-Adrenergic Receptor Is a Molecular Switch for Neuroendocrine Transdifferentiation of Prostate Cancer Cells

Author

Kristin Austlid Taskén, Anders Bjartell, Ian G. Mills, Aud Svindland, Wanzhong Wang, Kirsi Ketola, Andreas Engedal, Ingrid Jenny Guldvik, Heidi Kristin Nielsen, Alfonso Urbanucci, Helene Hartvedt Grytli, Håkon Ramberg, and Peder R. Braadland

Abstract

Supplementary Material and Methods, Supplementary Figure Legends, Supplementary Tables

Published
2023
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39. Supplemental Materials, Figures S1-6, Tables S1-4 from Regulator of Chromosome Condensation 2 Identifies High-Risk Patients within Both Major Phenotypes of Colorectal Cancer

Author

Bruun, Jarle, primary, Kolberg, Matthias, primary, Ahlquist, Terje C., primary, Røyrvik, Ellen C., primary, Nome, Torfinn, primary, Leithe, Edward, primary, Lind, Guro E., primary, Merok, Marianne A., primary, Rognum, Torleiv O., primary, Bjørkøy, Geir, primary, Johansen, Terje, primary, Lindblom, Annika, primary, Sun, Xiao-Feng, primary, Svindland, Aud, primary, Liestøl, Knut, primary, Nesbakken, Arild, primary, Skotheim, Rolf I., primary, and Lothe, Ragnhild A., primary

Published
2023
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48. The Movember Global Action Plan 1 (GAP1): Unique Prostate Cancer Tissue Microarray Resource

Author

Erickson A, Carlos S. Moreno, Michelle M. Kouspou, Fred Saad, Michael S. Lewis, Onur Ertunc, Adeboye O. Osunkoya, Colm Morrissey, Bigler Sa, Tuomas Mirtti, Anne-Marie Mes-Masson, Stephen J. Freedland, Zhou X, Igor Vidal, Aud Svindland, Larry True, Tracy Jones, Ouellet, Mark Buzza, Wiley K, Tasken Ka, Pekka Taimen, Isla P. Garraway, Ariel H Achtman, Bova Sg, Angelo M. De Marzo, Bruce J. Trock, Dominique Trudel, Berge, Tarja Lamminen, Beatrice S. Knudsen, Tampere University, BioMediTech, and TAYS Cancer Centre

Subjects
Male, Oncology, medicine.medical_specialty, Epidemiology, medicine.medical_treatment, 3122 Cancers, Disease, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, Prostate, Internal medicine, medicine, Humans, Lymph node, 030304 developmental biology, Prostatectomy, 0303 health sciences, Tissue microarray, business.industry, medicine.disease, 3. Good health, Androgen receptor, Prostatic Neoplasms, Castration-Resistant, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Biomarker (medicine), 3111 Biomedicine, business
Abstract

Background: The need to better understand the molecular underpinnings of the heterogeneous outcomes of patients with prostate cancer is a pressing global problem and a key research priority for Movember. To address this, the Movember Global Action Plan 1 Unique tissue microarray (GAP1-UTMA) project constructed a set of unique and richly annotated tissue microarrays (TMA) from prostate cancer samples obtained from multiple institutions across several global locations. Methods: Three separate TMA sets were built that differ by purpose and disease state. Results: The intended use of TMA1 (Primary Matched LN) is to validate biomarkers that help determine which clinically localized prostate cancers with associated lymph node metastasis have a high risk of progression to lethal castration-resistant metastatic disease, and to compare molecular properties of high-risk index lesions within the prostate to regional lymph node metastases resected at the time of prostatectomy. TMA2 (Pre vs. Post ADT) was designed to address questions regarding risk of castration-resistant prostate cancer (CRPC) and response to suppression of the androgen receptor/androgen axis, and characterization of the castration-resistant phenotype. TMA3 (CRPC Met Heterogeneity)'s intended use is to assess the heterogeneity of molecular markers across different anatomic sites in lethal prostate cancer metastases. Conclusions: The GAP1-UTMA project has succeeded in combining a large set of tissue specimens from 501 patients with prostate cancer with rich clinical annotation. Impact: This resource is now available to the prostate cancer community as a tool for biomarker validation to address important unanswered clinical questions around disease progression and response to treatment.

Published
2022
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49. Supplemental Materials, Figures S1-6, Tables S1-4 from Regulator of Chromosome Condensation 2 Identifies High-Risk Patients within Both Major Phenotypes of Colorectal Cancer

Author

Ragnhild A. Lothe, Rolf I. Skotheim, Arild Nesbakken, Knut Liestøl, Aud Svindland, Xiao-Feng Sun, Annika Lindblom, Terje Johansen, Geir Bjørkøy, Torleiv O. Rognum, Marianne A. Merok, Guro E. Lind, Edward Leithe, Torfinn Nome, Ellen C. Røyrvik, Terje C. Ahlquist, Matthias Kolberg, and Jarle Bruun

Abstract

Supplemental Materials, Figures S1-6, Tables S1-4. Fig. S1. Flow diagram for inclusion of patients in the study. Fig. S2. RNA secondary structure analysis of the 5'UTR RCC2 mutation compared to wild type. Fig. S3. Vector construction overview. Fig. S4. Morphological changes in actin fiber patterns following depletion of RCC2 protein in HCT15 cells. Fig. S5. Subgroup analyses of in situ protein expression of RCC2 for a consecutive CRC series. Fig. S6. Representative electropherograms from fragment analysis of the 5'UTR RCC2 mutation. Table S1. Statistics for relevant parameters for the test series (n = 37). Table S2. Statistics for relevant parameters for the validation series (n = 122). Table S3. Statistics for relevant parameters for the validation series (n = 60, R0 patients). Table S4. Primer and PCR details.

Published
2023
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50. Data from Regulator of Chromosome Condensation 2 Identifies High-Risk Patients within Both Major Phenotypes of Colorectal Cancer

Author

Ragnhild A. Lothe, Rolf I. Skotheim, Arild Nesbakken, Knut Liestøl, Aud Svindland, Xiao-Feng Sun, Annika Lindblom, Terje Johansen, Geir Bjørkøy, Torleiv O. Rognum, Marianne A. Merok, Guro E. Lind, Edward Leithe, Torfinn Nome, Ellen C. Røyrvik, Terje C. Ahlquist, Matthias Kolberg, and Jarle Bruun

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.

Published
2023
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