Regulator of chromosome condensation 2 identifies high-risk patients within both major phenotypes of colorectal cancer

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

Research output: Contribution to journalArticle

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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 highrisk 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.

Original languageEnglish (US)
Pages (from-to)3759-3770
Number of pages12
JournalClinical Cancer Research
Volume21
Issue number16
DOIs
StatePublished - Jan 1 2015

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Chromosomes, Human, Pair 2
Microsatellite Repeats
Colorectal Neoplasms
Phenotype
Neoplasms
Mutation
cdc Genes
5' Untranslated Regions
Rectal Neoplasms
Tumor Biomarkers
Cell Cycle Checkpoints
Luciferases
Reporter Genes
Colonic Neoplasms
Small Interfering RNA
Proteins
Research Design
Multivariate Analysis
Biomarkers
Immunohistochemistry

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Regulator of chromosome condensation 2 identifies high-risk patients within both major phenotypes of colorectal cancer. / Bruun, Jarle; Kolberg, Matthias; Ahlquist, Terje C.; Røyrvik, Ellen C.; Nome, Torfinn; Leithe, Edward; Lind, Guro E.; Merok, Marianne A.; Rognum, Torleiv O.; Bjørkøy, Geir; Johansen, Terje; Lindblom, Annika; Sun, Xiao Feng; Svindland, Aud; Liestøl, Knut; Nesbakken, Arild; Skotheim, Rolf I.; Lothe, Ragnhild A.

In: Clinical Cancer Research, Vol. 21, No. 16, 01.01.2015, p. 3759-3770.

Research output: Contribution to journalArticle

Bruun, Jarle ; Kolberg, Matthias ; Ahlquist, Terje C. ; Røyrvik, Ellen C. ; Nome, Torfinn ; Leithe, Edward ; Lind, Guro E. ; Merok, Marianne A. ; Rognum, Torleiv O. ; Bjørkøy, Geir ; Johansen, Terje ; Lindblom, Annika ; Sun, Xiao Feng ; Svindland, Aud ; Liestøl, Knut ; Nesbakken, Arild ; Skotheim, Rolf I. ; Lothe, Ragnhild A. / Regulator of chromosome condensation 2 identifies high-risk patients within both major phenotypes of colorectal cancer. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 16. pp. 3759-3770.
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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 highrisk 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.",
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T1 - Regulator of chromosome condensation 2 identifies high-risk patients within both major phenotypes of colorectal cancer

AU - Bruun, Jarle

AU - Kolberg, Matthias

AU - Ahlquist, Terje C.

AU - Røyrvik, Ellen C.

AU - Nome, Torfinn

AU - Leithe, Edward

AU - Lind, Guro E.

AU - Merok, Marianne A.

AU - Rognum, Torleiv O.

AU - Bjørkøy, Geir

AU - Johansen, Terje

AU - Lindblom, Annika

AU - Sun, Xiao Feng

AU - Svindland, Aud

AU - Liestøl, Knut

AU - Nesbakken, Arild

AU - Skotheim, Rolf I.

AU - Lothe, Ragnhild A.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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 highrisk 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.

AB - 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 highrisk 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.

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