Conservation of mononucleotide repeats within 3′ and 5′ untranslated regions and their instability in MSI-H colorectal cancer

Suraweera, Nirosha; Iacopetta, Barry; Duval, Alex; Compoint, Aurore; Tubacher, Emmanuel; Hamelin, Richard

doi:10.1038/sj.onc.1204952

Cited by 27 publications

(25 citation statements)

References 28 publications

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“…Figure 3, A-C shows the numbers of deletion mutations in their UTRs. MSs with longer repeat lengths exhibited a higher instability rate, which led to multiple nucleotide deletions (Suraweera et al 2001). Taken together, these results demonstrate that the number of candidate genes with MS mutations is markedly greater than had been previously known (Suraweera et al 2001;Kim et al 2002;Woerner et al 2003;Royrvik et al 2007;Shin et al 2011).…”

Section: Characterization Of Repeat Sequence Tract Instabilities In Gsupporting

confidence: 56%

Comprehensive genome- and transcriptome-wide analyses of mutations associated with microsatellite instability in Korean gastric cancers

et al. 2013

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Microsatellite instability (MSI) is a critical mechanism that drives genetic aberrations in cancer. To identify the entire MS mutation, we performed the first comprehensive genome-and transcriptome-wide analyses of mutations associated with MSI in Korean gastric cancer cell lines and primary tissues. We identified 18,377 MS mutations of five or more repeat nucleotides in coding sequences and untranslated regions of genes, and discovered 139 individual genes whose expression was down-regulated in association with UTR MS mutation. In addition, we found that 90.5% of MS mutations with deletions in gene regions occurred in UTRs. This analysis emphasizes the genetic diversity of MSI-H gastric tumors and provides clues to the mechanistic basis of instability in microsatellite unstable gastric cancers.

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Section: Characterization Of Repeat Sequence Tract Instabilities In Gsupporting

confidence: 56%

Comprehensive genome- and transcriptome-wide analyses of mutations associated with microsatellite instability in Korean gastric cancers

et al. 2013

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“…MNRs in UTRs are evolutionary conserved, indicating a functional role (20). Repeat sequences are prone to alteration in cancers with defect mismatch repair (MSI), and some of the alterations are involved in the regulation of gene and protein expression.…”

Section: Discussionmentioning

confidence: 99%

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

Bruun

Kolberg

Ahlquist

et al. 2015

Clinical Cancer Research

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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 ¼ 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 ¼ 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 0 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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“…In all cases the repeat was conserved, ie monomorphic. 10 Subsequently, 70 MSI-H colon tumour specimens were tested from patients complying with the clinical Bethesda criteria, 1 38 of whom a germ line mutation was identified in one of the MMR genes. MSI in the repeat was found in tumours from 12 of 20 (60%) hMLH1 patients, 6 of 12 (50%) hMSH2 patients, 2 of 6 (33%) hMSH6 patients, in 21 of 32 (66%) of the residual MSI-H tumours and in 4 of 4 (100%) MSI-H colon cancer cell lines.…”

Section: Resultsmentioning

confidence: 99%

Frequent mutations in the 3′-untranslated region of IFNGR1 lack functional impairment in microsatellite-unstable colorectal tumours

et al. 2008

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Microsatellite repeats are frequently found to be mutated in microsatellite-instable colorectal tumours. This suggests that these mutations are important events during tumour development. We have observed frequent mutations in microsatellite-instable (MSI-H) tumours and cell lines of a conserved A14 repeat within the 3 0 -untranslated region of the interferon-c receptor 1 gene (IFNGR1). The repeat was mutated in 59% (41 of 70) of colon carcinomas and in all four MSI-H colon cancer cell lines tested. In-vitro analysis of these cell lines did not show a decreased responsiveness to standard IFNc concentrations when compared to microsatellite-stable colon cancer cell lines. A functional consequence of the frequently found microsatellite instability in IFNGR1 is therefore not evident.

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Conservation of mononucleotide repeats within 3′ and 5′ untranslated regions and their instability in MSI-H colorectal cancer

Cited by 27 publications

References 28 publications

Comprehensive genome- and transcriptome-wide analyses of mutations associated with microsatellite instability in Korean gastric cancers

Comprehensive genome- and transcriptome-wide analyses of mutations associated with microsatellite instability in Korean gastric cancers

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

Frequent mutations in the 3′-untranslated region of IFNGR1 lack functional impairment in microsatellite-unstable colorectal tumours

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