Molecular lesions in colorectal cancer: impact on prognosis?

Klump, Bodo; Nehls, Oliver; Okech, Thomas; Hsieh, Chih-Jen; Gaco, Vera; Gittinger, F. S.; Sarbia, Mario; Borchard, F; Greschniok, A; Gruenagel, H. H.; Porschen, Rainer; Gregor, Michael

doi:10.1007/s00384-003-0499-7

Cited by 72 publications

(61 citation statements)

References 119 publications

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“…[2][3][4] To determine whether Skp2 or Cks1 expressions could provide additional information to that given by p27 Kip1 alone, the authors of the current study explored the survival Kaplan-Meier test for Skp2 or Cks1 after having stratified for p27 Kip1 . As expected, patients with low p27 Kip1 levels and high Skp2 levels had low overall survival rates with a mean survival rate of 32 months (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Numerous stud-ies have suggested that the differences observed in patients' outcome, despite similar clinical and histologic disease, may be the result of alterations in the normal regulation of specific biologic and cellular events (reviewed by Klump, et al). 2 Mutations of various tumor suppressor oncogenes such as p53, k-ras, and DCC (deleted in colorectal carcinoma) are frequently found in colorectal carcinoma, and these are commonly associated with aggressive tumor behavior and poor prognosis. 2 Nevertheless, not one of these biologic factors is accepted as a singular, universal, prognostic marker, and thus, great benefit is likely to result from the characterization of additional biologic prognostic factors.…”

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confidence: 99%

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The prognostic impact of the ubiquitin ligase subunits Skp2 and Cks1 in colorectal carcinoma

Shapira

Ben‐Izhak

Linn

et al. 2005

Cancer

132

112

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BACKGROUNDLoss of the cell‐cycle inhibitory protein p27Kip1 is associated with poor prognosis in colorectal carcinoma. The decrease in p27Kip1 levels is the result of increased proteasome‐dependent degradation, mediated and rate‐limited by its specific ubiquitin ligase subunits S‐phase kinase protein (Skp) 2 and cyclin‐dependent kinase subunit (Cks) 1. Recently, Skp2 and Cks1 expression were found to be increased in some colorectal carcinomas, but their potential role as prognostic markers for survival is unknown. The present study was undertaken to assess the prognostic value of both Skp2 and Cks1 in colorectal carcinoma.MATERIALS AND METHODSThe expression of Skp2, Cks1, and p27Kip1 was examined by immunohistochemistry using highly specific antibodies on formalin‐fixed, paraffin‐embedded tissue sections from 80 patients with colorectal carcinoma.RESULTSOverexpression of Skp2 and Cks1 strongly correlated with loss of p27Kip1 and loss of tumor differentiation. A significant decrease in overall survival was observed in patients expressing high Skp2 or Cks1 levels, and in particular, patients with Stage II and III disease. Each protein provided significant additional prognostic information to that given by disease stage, tumor grade, or p27Kip1 expression.CONCLUSIONSResults suggest that overexpression of Skp2 or Cks1 is strongly associated with poor prognosis and may thus be used as prognostic markers for overall survival in colorectal carcinoma. Cancer 2005. © 2005 American Cancer Society.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

The prognostic impact of the ubiquitin ligase subunits Skp2 and Cks1 in colorectal carcinoma

Shapira

Ben‐Izhak

Linn

et al. 2005

Cancer

132

112

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“…Interestingly, the inclusion of the microsatellite-unstable tumors in the group of tumors without 18q LOH has demonstrated a significant prognostic relevance in the largest patient series investigated so far for chromosome 18q status. 25 Moreover, a large number of studies have demonstrated that microsatellite instability phenotype is a predictive marker of good prognosis and differential response to adjuvant chemotherapy. 25 More recently, microsatellite instability status, as determined by immunohistochemistry, has been demonstrated as an independent predictive factor of good prognosis in T3N0M0 colon cancer.…”

Section: Discussionmentioning

confidence: 99%

“…25 Moreover, a large number of studies have demonstrated that microsatellite instability phenotype is a predictive marker of good prognosis and differential response to adjuvant chemotherapy. 25 More recently, microsatellite instability status, as determined by immunohistochemistry, has been demonstrated as an independent predictive factor of good prognosis in T3N0M0 colon cancer. 26 In this context, microsatellite analysis of chromosome 18q may segregate patients into subsets of good and bad prognosis by detecting both LOH and microsatellite instability, in concert with other microsatellite instability analysis/criteria.…”

Section: Discussionmentioning

confidence: 99%

A Novel Multiplexing, Polymerase Chain Reaction-Based Assay for the Analysis of Chromosome 18q Status in Colorectal Cancer

Erill

Colomer

Calvo

et al. 2005

The Journal of Molecular Diagnostics

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Chromosome 18q allelic loss has been reported to have prognostic significance in stage II colorectal carcinoma. We have developed a fluorescent multiplex polymerase chain reaction assay to analyze five microsatellite markers (D18S55, D18S58, D18S61, D18S64, and D18S69) for allelic loss at the long arm of chromosome 18. Amplicon detection and evaluation was accomplished by capillary electrophoresis using an ABI 310 genetic analyzer. Robustness of the assay when performed on DNA extracted from formalinfixed, paraffin-embedded tissue sections was confirmed by analyzing its repeatability and reproducibility. Allelic loss was assessed in 61 stage II colorectal tumors and was detected in 58% (31 of 53) of tumors not showing instability. As part of the study, results of 207 previous polymerase chain reaction/polyacrylamide-based assays were re-evaluated by two independent observers to determine the degree of concordance of visual evaluation. In the case of stage II colorectal tumors, when electropherogram results were compared with those obtained from visual evaluation of the same markers after polyacrylamide gel electrophoresis, discrepancies between observers were detected in 16.4% of determinations. In conclusion, we have developed a robust and reliable assay for multiplexed loss of heterozygosity determination that improves assessment of chromosome 18q allelic loss in colorectal tumors processed as routine formalin-fixed, paraffin-embedded specimens. The prognosis of colorectal cancer is mainly based on tumor stage at time of diagnosis. However, other clinicopathological features such as tumor location, perineural invasion, lymphatic vessel invasion and differentiation, as well as certain molecular alterations such as microsatellite instability, have also been reported to be predictors of tumor recurrence and patient outcome. 1,2 Survival for patients with tumors confined to the muscularis propria (stage I) or with extensive metastatic disease (stage IV) is predictable; however, tumor biological behavior after surgical treatment for stage II and III tumors is not well established. Approximately 30% of patients with stage II colon cancer will relapse and die of the disease. [3][4][5][6] More significantly, up to 65% of patients with stage III tumors will succumb to colon cancer. The use of adjuvant therapies in patients with stage II lesions is not exempt of controversy. These therapies have sideeffects, and should be given to those patients who would benefit from them. 7 Prognostic markers that complement standard clinical and pathological staging further stratify stage II patients into high-risk and lowrisk groups of relapse after surgery, and better guide adjuvant therapy. Biological factors that account for the different outcome among patients presenting with the same clinical stage are still poorly understood, but several studies have revealed the prognostic significance of 18q allelic loss in stage II colorectal carcinomas. 3,5,6,8 -10 Loss of this region, from which several tumor suppressor genes have been c...

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“…4,5 In addition, a multitude of molecular alterations of genes have been described in the literature as being associated with development and prognosis of CRC. The potential complexity of genetic alterations in tumors renders microarray-based gene expression profiling a powerful tool for obtaining information about the molecular background of CRC, for establishing a relationship between the clinical and pathological stages and for discrimination of cellular conditions.…”

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confidence: 99%

Transcriptional census of 36 microdissected colorectal cancers yields a gene signature to distinguish UICC II and III

Groene

Mansmann

Meister

et al. 2006

Intl Journal of Cancer

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UICC stage II and III colorectal cancers (CRC) differ fundamentally in prognosis and therapeutic concepts. To analyze differential gene expression between both stages and to establish a relationship between molecular background and clinical presentation, tumor material from 36 unselected consecutive patients presenting with sporadic CRC, 18 UICC stage II and 18 UICC stage III, were laser microdissected to separate epithelial tumor cells. Gene expression levels were measured using U133A Affymetrix gene arrays. Twelve CRC associated signal transduction pathways as well as all 22,000 probe sets were screened for differential gene expression. We identified a signature consisting of 45 probe sets that allowed discrimination between UICC stage II and stage III with a rate of correct classification of about 80%. The most distinctive elements in this signature were the gene GSTP-binding elongation factor (GSPT2) and the transcription factor HOXA9. Differential expression of these genes was confirmed by quantitative real-time polymerase chain reaction (p (HOXA9) 5 0.04, p (GSTP2) 5 0.02). Despite the reliability of the presented data, there was no substantial differential expression of genes in cancer-related pathways. However, the comparison with recently published data corroborates the 45 gene signature showing structural agreement in the direction of fold changes of gene expression levels for our set of genes chosen to discriminate between both stages. ' 2006 Wiley-Liss, Inc.Key words: colorectal cancer; gene expression analysis; gene signature; classification; UICC stage II; UICC stage III In colorectal cancer (CRC), the prognosis and the type of adjuvant treatment is highly dependent upon the stage of disease. The current staging of CRC is predominantly based on clinical and pathological parameters such as local tumor extension, lymph node involvement and distant metastases. 1,2 More than 70% of patients with curative resection of CRC are classified as UICC stage II and III. While UICC stage II CRC is generally considered to be local and less aggressive with 5-year recurrence rates of 20-25%, tumors of stage UICC III are more dynamic by spreading metastases to lymph nodes. This results in a 5-year recurrence rate of more than 40% after radical resection 3 and constitutes the reason for recommendation of adjuvant therapy.

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Molecular lesions in colorectal cancer: impact on prognosis?

Abstract: Considering also our own findings, this review presents the latest developments in the scientific discussion of the tumor suppressor/oncogenes p53, k-ras, and DCC, biochemical determinants of the 5-fluorouracil metabolism, and defects of the DNA repair system.

Cited by 72 publications

References 119 publications

The prognostic impact of the ubiquitin ligase subunits Skp2 and Cks1 in colorectal carcinoma

The prognostic impact of the ubiquitin ligase subunits Skp2 and Cks1 in colorectal carcinoma

A Novel Multiplexing, Polymerase Chain Reaction-Based Assay for the Analysis of Chromosome 18q Status in Colorectal Cancer

Transcriptional census of 36 microdissected colorectal cancers yields a gene signature to distinguish UICC II and III

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