Pathogenesis of DNA repair-deficient cancers: a statistical meta-analysis of putative Real Common Target genes

Woerner, Stefan M.; Benner, Axel; Sutter, Christian; Schiller, Marian; Yuan, Yan P.; Keller, Gisela; Bork, Peer; Doeberitz, Magnus von Knebel; Gebert, Johannes

doi:10.1038/sj.onc.1206421

Cited by 144 publications

(143 citation statements)

References 30 publications

(45 reference statements)

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“…There have, however, been some estimates of the mutation frequencies in coding microsatellites of the genes contributing to tumor development (target genes) (Boland et al, 1998;Perucho, 1999a, b;Duval et al, 2001Duval et al, , 2002Zhang et al, 2001;Suzuki et al, 2002;Woerner et al, 2003), which appears to depend largely on the length of the repeat (Kunkel et al, 1994;Chen et al, 1995). According to statistical analyses describing the relationship between the mutation frequency and the relevance to tumor development, the frequency of the mutations in coding microsatellites in bystander genes (not related to tumorigenesis) are no higher than the frequency of mutations in non-coding microsatellites of the same length and type (Duval et al, 2002;Woerner et al, 2003). The frequency of mutations seen in many noncoding repeats that are less than nine mononucleotides, has been shown to be lower than 6% (Suzuki et al, 2002) and so the mutations seen in the RBM35A gene, for example, are less likely to be due to a bystander effect, as this gene was mutated in 25% of primary tumors with MSI (Table 2 and Figure 5).…”

Section: Discussionmentioning

confidence: 99%

Identifying candidate colon cancer tumor suppressor genes using inhibition of nonsense-mediated mRNA decay in colon cancer cells

Ivanov

Hawthorn

et al. 2006

Oncogene

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Inhibition of the nonsense-mediated decay (NMD) mechanism in cells results in stabilization of transcripts carrying premature translation termination codons. A strategy referred to as gene identification by NMD inhibition (GINI) has been proposed to identify genes carrying nonsense mutations. Genes containing frameshift mutations in colon cancer cell line have been identified using a modified version of GINI. To increase the efficiency of identifying mutant genes using GINI, we have now further improved the strategy. In this approach, inhibition of NMD with emetine is complemented with inhibiting NMD by blocking the phosphorylation of the hUpf1 protein with caffeine. In addition, to enhance the GINI strategy, comparing mRNA level alterations produced by inhibiting transcription alone or inhibiting transcription together with NMD following caffeine pretreatment were used for the efficient identification of false positives produced as a result of stress response to NMD inhibition. To demonstrate the improved efficiency of this approach, we analysed colon cancer cell lines showing microsatellite instability. Bi-allelic inactivating mutations were found in the FXR1, SEC31L1, NCOR1, BAT3, PHF14, ZNF294, C19ORF5 genes as well as genes coding for proteins with yet unknown functions.

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Section: Discussionmentioning

confidence: 99%

Identifying candidate colon cancer tumor suppressor genes using inhibition of nonsense-mediated mRNA decay in colon cancer cells

Ivanov

Hawthorn

et al. 2006

Oncogene

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“…The dependency of the mutation rate on the repeat length was modeled using a general four-parameter sigmoid nonlinear regression model as suggested previously (18).…”

Section: Statistical Regression Analysismentioning

confidence: 99%

Mutations in the Circadian Gene CLOCK in Colorectal Cancer

Alhopuro

Björklund

Sammalkorpi

et al. 2010

Molecular Cancer Research

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The circadian clock regulates daily variations in physiologic processes. CLOCK acts as a regulator in the circadian apparatus controlling the expression of other clock genes, including PER1. Clock genes have been implicated in cancer-related functions; in this work, we investigated CLOCK as a possible target of somatic mutations in microsatellite unstable colorectal cancers. Combining microarray gene expression data and public gene sequence information, we identified CLOCK as 1 of 790 putative novel microsatellite instability (MSI) target genes. A total of 101 MSI colorectal carcinomas (CRC) were sequenced for a coding microsatellite in CLOCK. The effect of restoring CLOCK expression was studied in LS180 cells lacking wild-type CLOCK by stably expressing GST-CLOCK or glutathione S-transferase empty vector and testing the effects of UV-induced apoptosis and radiation by DNA content analysis using flow cytometry. Putative novel CLOCK target genes were searched by using ChIP-seq. CLOCK mutations occurred in 53% of MSI CRCs. Restoring CLOCK expression in cells with biallelic CLOCK inactivation resulted in protection against UV-induced apoptosis and decreased G 2 -M arrest in response to ionizing radiation. Using ChIP-Seq, novel CLOCK-binding elements were identified near DNA damage genes p21, NBR1, BRCA1, and RAD50. CLOCK is shown to be mutated in cancer, and altered response to DNA damage provides one plausible mechanism of tumorigenesis. Mol Cancer Res; 8(7); 952-60. ©2010 AACR.

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“…HNPCC is an autosomal dominantly inherited disorder of cancer susceptibility (mostly colorectal and endometrial cancer) caused by a germline mutation in one of the mismatch repair (MMR) genes (Peltoma¨ki and Vasen, 1997). The underlying mechanism of MMR-deficient tumour carcinogenesis reflects the accumulation of somatic frameshift mutations at repeated sequences located within the coding regions of target genes involved in key cellular pathways (Duval and Hamelin, 2002;Woerner et al, 2003). The process involved in the selection of target genes appears to be somehow tissue-specific, with the mutation profiles differing between gynaecological and gastrointestinal cancers Woerner et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…BAX, a proapoptotic member of the Bcl-2 family, is one of the most frequently inactivated genes in MSI colon carcinomas. Its deficiency has been A10 A9 G8 C8 A8 A10 T8 A8 A9 T11 A9 A10 A total of 13 target genes, chosen either because they were frequent targets for MSI-driven mutations in MSI tumours of various locations or because they play key roles in the maintenance of the genome integrity, were investigated at multiple tumour sites in MSI UUT tumours (Duval & Hamelin, 2002;Woerner et al, 2003). With the exception of MRE11, all mononucleotide repeats studied were located in the coding sequence, where insertion/deletion mutations lead to the synthesis of a truncated protein.…”

Section: Introductionmentioning

confidence: 99%

“…shown to accelerate tumour growth and decrease apoptosis (Rampino et al, 1997;Ionov et al, 2000;Duval and Hamelin, 2002;Woerner et al, 2003). MRE11 and RAD50, two genes frequently altered in MSI gastrointestinal tumours, forms together with NBS1 a complex that plays a major role in DNA damage signalling, DNA repair and cell cycle control (Kim et al, 2001;Giannini et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Microsatellite instability and mutation analysis of candidate genes in urothelial cell carcinomas of upper urinary tract

Mongiat-Artus

Miquel²,

et al. 2005

Oncogene

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A subset of upper urinary tract urothelial cell carcinomas (UUC), arising sporadically or as a manifestation of hereditary non-polyposis colorectal cancer, displays microsatellite instability (MSI). MSI tumours are characterized by defective mismatch repair and accumulation of frameshift mutations in numerous genes harbouring repeats in their coding sequences. We have evaluated the incidence of MSI in UUC and the intratumoral distribution of mutations in 13 candidate target genes. A total of 58 unselected UUC were screened for MSI using the panel of five mononucleotide markers recently recommended by the National Cancer Institute for a precise MSI assessment. Four tumours displayed MSI (7%), among which at least three had alterations in the genes MSH3, BAX, MRE11, RAD50. Mutations in genes involved in key cellular pathways (ATR, DNA-PKcs, MBD4, TCF-4, MSH6, and BLM) were further detected. BAX and MRE11 mutations tend to present homogeneously within the three MSI UUC. Immunohistochemistry (MLH1, MSH2, MSH6) showed that loss of mismatch repair protein expression occurred in all MSI UUC defining the gene defect and that MRE11 and RAD50 mutations were associated with their concomitant loss expression. In conclusion, MSI UUC represent a small proportion of UUC in which BAX and MRE11 mutations are frequent and may play a role early in UUC tumorigenesis.

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Pathogenesis of DNA repair-deficient cancers: a statistical meta-analysis of putative Real Common Target genes

Cited by 144 publications

References 30 publications

Identifying candidate colon cancer tumor suppressor genes using inhibition of nonsense-mediated mRNA decay in colon cancer cells

Identifying candidate colon cancer tumor suppressor genes using inhibition of nonsense-mediated mRNA decay in colon cancer cells

Mutations in the Circadian Gene CLOCK in Colorectal Cancer

Microsatellite instability and mutation analysis of candidate genes in urothelial cell carcinomas of upper urinary tract

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