Genetic imbalances with impact on survival in colorectal cancer patients

Knösel, Thomas; Schlüns, Karsten; Stein, Ulf; Schwabe, Holger; Schlag, Peter M.; Dietel, Manfred; Petersen, Iver

doi:10.1046/j.1365-2559.2003.01720.x

Cited by 31 publications

(22 citation statements)

References 45 publications

(47 reference statements)

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“…The results of our PAM and SAM analyses are not dissimilar to those recently reported by Knosel et al (38). In the latter study, using conventional CGH, loss of 18q or gain of 20q was associated with significantly longer disease-free survival.…”

Section: Discussionsupporting

confidence: 76%

Fractional Genomic Alteration Detected by Array-Based Comparative Genomic Hybridization Independently Predicts Survival after Hepatic Resection for Metastatic Colorectal Cancer

Mehta¹,

Nakao

Zuraek³

et al. 2005

Clinical Cancer Research

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Purpose: Although liver resection is the primary curative therapy for patients with colorectal hepatic metastases, most patients have a recurrence. Identification of molecular markers that predict patients at highest risk for recurrence may help to target further therapy.Experimental Design: Array-based comparative genomic hybridization was used to investigate the association of DNA copy number alterations with outcome in patients with colorectal liver metastasis resected with curative intent. DNA from 50 liver metastases was labeled and hybridized onto an array consisting of 2,463 bacterial artificial chromosome clones covering the entire genome. The total fraction of genome altered (FGA) in the metastases and the patient's clinical risk score (CRS) were calculated to identify independent prognostic factors for survival.Results: An average of 30 F F14% of the genome was altered in the liver metastases (14% gained and 16% lost). As expected, a lower CRS was an independent predictor of overall survival (P = = 0.03). In addition, a high FGA also was an independent predictor of survival (P = = 0.01). The median survival time in patients with a low CRS (score 0-2) and a high (z z20%) FGA was 38 months compared with 18 months in patients with a low CRS and a low FGA. Supervised analyses, using Prediction Analysis of Microarrays and Significance Analysis of Microarrays, identified a set of clones, predominantly located on chromosomes 7 and 20, which best predicted survival.Conclusions: Both FGA and CRS are independent predictors of survival in patients with resected hepatic colorectal cancer metastases. The greater the FGA, the more likely the patient is to survive.

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Section: Discussionsupporting

confidence: 76%

Fractional Genomic Alteration Detected by Array-Based Comparative Genomic Hybridization Independently Predicts Survival after Hepatic Resection for Metastatic Colorectal Cancer

Mehta¹,

Nakao

Zuraek³

et al. 2005

Clinical Cancer Research

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“…losses of 1p, 3p, 8p, 9q, 12q, 17q, 19p, 21q21 and 22q and gains at 2q, 5p and chromosome 6 have already been associated with tumor progression and dissemination in colon cancer [5,[10][11][12][13] or other cancer types [6,14,15]. Similarly, many candidate genes of common alterated regions in lung and liver metastases were already described, e.g.…”

Section: Discussionmentioning

confidence: 99%

Chromosomal Alterations in Lung Metastases of Colorectal Carcinomas: Associations with Tissue Specific Tumor Dissemination

Knösel¹,

Schlüns²,

Dietel³

et al. 2005

Clin Exp Metastasis

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Comparative genomic hybridization was used to screen colorectal carcinomas for chromosomal aberrations that are associated with the metastatic phenotype of the lung. Specimens of 13 lung metastases, 6 primary tumors, 1 lymph node metastasis, 1 liver metastasis, and 1 ovarian metastasis were investigated and added to our CGH colon cancer tumor collective, comprising 85 tumor specimens from 56 patients (see CGH online tumor database at http://amba.charite.de/cgh). Lung metastases showed more alterations than liver metastases, particularly more deletions at 1p, 3p, 9q, 12q, 17q, 19p and 22q and gains at 2q, 5p, and chromosome 6. Comparing lung metastases with their corresponding primary tumors, particularly more deletions at 3p, 8p, 12q, 17q, and 21q21 and gains at 5p were observed. Based on our results, we wish to suggest a metastatic progression model. Specific subpopulations of metastatic cells have a distinct metastatic potential, which is reflected by a non-random accumulation of chromosomal alterations. Distinct alterations already exist within the primary tumor and this "ready to go package" gives the cells the metastatic potential to achieve the complex series of events needed for metastasis.

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“…Although RNPC1 is found to be overexpressed in various cancers (Korn et al 1999;Tanner et al 2000;Zheng et al 2001;Bar-Shira et al 2002;Hermsen et al 2002;Krackhardt et al 2002;Knosel et al 2003;Ginestier et al 2006;Letessier et al 2006;Carvalho et al 2009), its oncogenic activity has not been defined. Our molecular studies indicate that RNPC1 inhibits p53 translation and, consequently, p53 protein expression.…”

Section: The Role Of Rnpc1 In Tumorigenesismentioning

confidence: 99%

“…The RNPC1 gene is located on chromosome 20q13, a site frequently amplified in breast cancer Letessier et al 2006), prostate cancer (Zheng et al 2001;Bar-Shira et al 2002), ovarian cancer (Tanner et al 2000), colorectal cancer (Korn et al 1999;Knosel et al 2003), and chronic lymphocytic leukemia (Krackhardt et al 2002). In addition, RNPC1 overexpression is found to promote the transition of colorectal adenoma to carcinoma (Hermsen et al 2002;Carvalho et al 2009).…”

mentioning

confidence: 99%

Translational repression of p53 by RNPC1, a p53 target overexpressed in lymphomas

Zhang¹,

Cho²,

Shu³

et al. 2011

Genes Dev.

117

183

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The p53 pathway is critical for tumor suppression, as the majority of human cancer has a faulty p53. Here, we identified RNPC1, a p53 target and a RNA-binding protein, as a critical regulator of p53 translation. We showed that ectopic expression of RNPC1 inhibited, whereas knockdown of RNPC1 increased, p53 translation under normal and stress conditions. We also showed that RNPC1 prevented cap-binding protein eIF4E from binding p53 mRNA via its C-terminal domain for physical interaction with eIF4E, and its N-terminal domain for binding p53 mRNA. Consistent with this, we found that RNPC1 directly binds to p53 59 and 39untranslated regions (UTRs). Importantly, we showed that RNPC1 inhibits ectopic expression of p53 in a dose-dependent manner via p53 59 or 39 UTR. Moreover, we showed that loss of RNPC1 in mouse embryonic fibroblasts increased the level of p53 protein, leading to enhanced premature senescence in a p53-dependent manner. Finally, to explore the clinical relevance of our finding, we showed that RNPC1 was frequently overexpressed in dog lymphomas, most of which were accompanied by decreased expression of wild-type p53. Together, we identified a novel p53-RNPC1 autoregulatory loop, and our findings suggest that RNPC1 plays a role in tumorigenesis by repressing p53 translation.

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Genetic imbalances with impact on survival in colorectal cancer patients

Abstract: These five markers allow a molecular categorization of patients into high and low clinical risk groups. Thus, the genomic data have refined the histopathological classification highlighting the necessity for a supplementary genetically based stratification of colorectal cancer.

Cited by 31 publications

References 45 publications

Fractional Genomic Alteration Detected by Array-Based Comparative Genomic Hybridization Independently Predicts Survival after Hepatic Resection for Metastatic Colorectal Cancer

Fractional Genomic Alteration Detected by Array-Based Comparative Genomic Hybridization Independently Predicts Survival after Hepatic Resection for Metastatic Colorectal Cancer

Chromosomal Alterations in Lung Metastases of Colorectal Carcinomas: Associations with Tissue Specific Tumor Dissemination

Translational repression of p53 by RNPC1, a p53 target overexpressed in lymphomas

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