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  • 1
    Online Resource
    Online Resource
    Genetic Amplification of the NOTCH Modulator LNX2 Upregulates the WNT/β-Catenin Pathway in Colorectal Cancer
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 6 ( 2013-03-15), p. 2003-2013
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 6 ( 2013-03-15), p. 2003-2013
    Abstract: Chromosomal copy number alterations (aneuploidy) define the genomic landscape of most cancer cells, but identification of the oncogenic drivers behind these imbalances remains an unfinished task. In this study, we conducted a systematic analysis of colorectal carcinomas that integrated genomic copy number changes and gene expression profiles. This analysis revealed 44 highly overexpressed genes mapping to localized amplicons on chromosome 13, gains of which occur often in colorectal cancers (CRC). RNA interference (RNAi)–mediated silencing identified eight candidates whose loss-of-function reduced cell viability 20% or more in CRC cell lines. The functional space of the genes NUPL1, LNX2, POLR1D, POMP, SLC7A1, DIS3, KLF5, and GPR180 was established by global expression profiling after RNAi exposure. One candidate, LNX2, not previously known as an oncogene, was involved in regulating NOTCH signaling. Silencing LNX2 reduced NOTCH levels but also downregulated the transcription factor TCF7L2 and markedly reduced WNT signaling. LNX2 overexpression and chromosome 13 amplification therefore constitutively activates the WNT pathway, offering evidence of an aberrant NOTCH–WNT axis in CRC. Cancer Res; 73(6); 2003–13. ©2012 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-12-3159
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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    detail.hit.zdb_id: 410466-3
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  • 2
    Online Resource
    Online Resource
    A genomic strategy for the functional validation of colorectal cancer genes identifies potential therapeutic targets
    Wiley ; 2011
    In:  International Journal of Cancer Vol. 128, No. 5 ( 2011-03), p. 1069-1079
    Details
    In: International Journal of Cancer, Wiley, Vol. 128, No. 5 ( 2011-03), p. 1069-1079
    Abstract: Genes that are highly overexpressed in tumor cells can be required for tumor cell survival and have the potential to be selective therapeutic targets. In an attempt to identify such targets, we combined a functional genomics and a systems biology approach to assess the consequences of RNAi‐mediated silencing of overexpressed genes that were selected from 140 gene expression profiles from colorectal cancers (CRCs) and matched normal mucosa. In order to identify credible models for in‐depth functional analysis, we first confirmed the overexpression of these genes in 25 different CRC cell lines. We then identified five candidate genes that profoundly reduced the viability of CRC cell lines when silenced with either siRNAs or short‐hairpin RNAs (shRNAs), i.e. , HMGA1 , TACSTD2 , RRM2 , RPS2 and NOL5A . These genes were further studied by systematic analysis of comprehensive gene expression profiles generated following siRNA‐mediated silencing. Exploration of these RNAi‐specific gene expression signatures allowed the identification of the functional space in which the five genes operate and showed enrichment for cancer‐specific signaling pathways, some known to be involved in CRC. By comparing the expression of the RNAi signature genes with their respective expression levels in an independent set of primary rectal carcinomas, we could recapitulate these defined RNAi signatures, therefore, establishing the biological relevance of our observations. This strategy identified the signaling pathways that are affected by the prominent oncogenes HMGA1 and TACSTD2 , established a yet unknown link between RRM2 and PLK1 and identified RPS2 and NOL5A as promising potential therapeutic targets in CRC.
    Type of Medium: Online Resource
    ISSN: 0020-7136 , 1097-0215
    URL: Issue
    URL: Article
    DOI: 10.1002/ijc.v128.5
    DOI: 10.1002/ijc.25453
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2011
    detail.hit.zdb_id: 218257-9
    detail.hit.zdb_id: 1474822-8
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  • 3
    Online Resource
    Online Resource
    Chromosomal Breakpoints in Primary Colon Cancer Cluster at Sites of Structural Variants in the Genome
    American Association for Cancer Research (AACR) ; 2008
    In:  Cancer Research Vol. 68, No. 5 ( 2008-03-01), p. 1284-1295
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 68, No. 5 ( 2008-03-01), p. 1284-1295
    Abstract: Genomic aberrations on chromosome 8 are common in colon cancer, and are associated with lymph node and distant metastases as well as with disease susceptibility. This prompted us to generate a high-resolution map of genomic imbalances of chromosome 8 in 51 primary colon carcinomas using a custom-designed genomic array consisting of a tiling path of BAC clones. This analysis confirmed the dominant role of this chromosome. Unexpectedly, the position of the breakpoints suggested colocalization with structural variants in the human genome. In order to map these sites with increased resolution and to extend the analysis to the entire genome, we analyzed a subset of these tumors (n = 32) by comparative genomic hybridization on a 185K oligonucleotide array platform. Our comprehensive map of the colon cancer genome confirmed recurrent and specific low-level copy number changes of chromosomes 7, 8, 13, 18, and 20, and unveiled additional, novel sites of genomic imbalances including amplification of a histone gene cluster on chromosome 6p21.1-21.33 and deletions on chromosome 4q34-35. The systematic comparison of segments of copy number change with gene expression profiles showed that genomic imbalances directly affect average expression levels. Strikingly, we observed a significant association of chromosomal breakpoints with structural variants in the human genome: 41% of all copy number changes occurred at sites of such copy number variants (P & lt; 2.2e−16). Such an association has not been previously described and reveals a yet underappreciated plasticity of the colon cancer genome; it also points to potential mechanisms for the induction of chromosomal breakage in cancer cells. [Cancer Res 2008;68(5):1284–95]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-07-2864
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2008
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  • 4
    Online Resource
    Online Resource
    Gene Expression Profiling Reveals a Massive, Aneuploidy-Dependent Transcriptional Deregulation and Distinct Differences between Lymph Node–Negative and Lymph Node–Positive Colon Carcinomas
    American Association for Cancer Research (AACR) ; 2007
    In:  Cancer Research Vol. 67, No. 1 ( 2007-01-01), p. 41-56
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 67, No. 1 ( 2007-01-01), p. 41-56
    Abstract: To characterize patterns of global transcriptional deregulation in primary colon carcinomas, we did gene expression profiling of 73 tumors [Unio Internationale Contra Cancrum stage II (n = 33) and stage III (n = 40)] using oligonucleotide microarrays. For 30 of the tumors, expression profiles were compared with those from matched normal mucosa samples. We identified a set of 1,950 genes with highly significant deregulation between tumors and mucosa samples (P & lt; 1e−7). A significant proportion of these genes mapped to chromosome 20 (P = 0.01). Seventeen genes had a & gt;5-fold average expression difference between normal colon mucosa and carcinomas, including up-regulation of MYC and of HMGA1, a putative oncogene. Furthermore, we identified 68 genes that were significantly differentially expressed between lymph node–negative and lymph node–positive tumors (P & lt; 0.001), the functional annotation of which revealed a preponderance of genes that play a role in cellular immune response and surveillance. The microarray-derived gene expression levels of 20 deregulated genes were validated using quantitative real-time reverse transcription-PCR in & gt;40 tumor and normal mucosa samples with good concordance between the techniques. Finally, we established a relationship between specific genomic imbalances, which were mapped for 32 of the analyzed colon tumors by comparative genomic hybridization, and alterations of global transcriptional activity. Previously, we had conducted a similar analysis of primary rectal carcinomas. The systematic comparison of colon and rectal carcinomas revealed a significant overlap of genomic imbalances and transcriptional deregulation, including activation of the Wnt/β-catenin signaling cascade, suggesting similar pathogenic pathways. [Cancer Res 2007;67(1):41–56]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-06-1514
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2007
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  • 5
    Online Resource
    Online Resource
    Detection of early-stage pancreatic ductal adenocarcinoma (PDAC): Sensitivity, specificity, and discriminatory properties of the serum-based PAM4-immunoassay.
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 4_suppl ( 2012-02-01), p. 151-151
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 4_suppl ( 2012-02-01), p. 151-151
    Abstract: 151 Background: We recently reported that a serum-based enzyme immunoassay employing the PAM4 antibody was able to correctly identify 82% of patients with known PDAC and, importantly, that this assay had promising sensitivity for detecting early-stage disease. We now extend these findings in a much larger patient population that includes over 600 sera from both malignant and benign diseases of the pancreas and surrounding tissues. Methods: In a blinded analysis, sera from patients with confirmed PDAC (N=298), other cancers (N=99), benign disease of the pancreas (N=126), and healthy adults (N=79) were evaluated by enzyme immunoassay for concentration of PAM4-antigen levels. Results: Overall sensitivity for detection of PDAC was 76%, with 64% of stage-1 patients testing positive and a higher sensitivity (85%) for advanced disease. For the most part, sera from patients with neuroendocrine tumors of the pancreas or cancers of other origin (squamous, GIST, etc.) did not have elevated levels of the PAM4-antigen. Approximately half of the patients with ampullary (48%) and extrahepatic biliary (50%) adenocarcinomas had positive levels of circulating PAM4-antigen. Of 126 patients diagnosed with benign conditions of the pancreas, only 24 (19%) were positive and, in particular, 18 of 80 (23%) patients with chronic pancreatitis (CP) were positive. ROC curve analysis demonstrated a statistically significant difference between the PDAC and CP groups (P 〈 0.0001), with an area under the curve of 0.84 ± 0.02 (95% CI: 0.79 – 0.89). The positive- and negative-likelihood ratios for differentiating PDAC from benign conditions of the pancreas were 4.00 and 0.30, respectively. Conclusions: The PAM4-immunoassay detects nearly two-thirds of stage-1 PDAC patients, and does so with high discriminatory power with respect to benign pancreatic disease. Our results provide a rationale for longitudinal surveillance of patients considered at high-risk for PDAC (e.g., familial pancreatic cancer, new-onset diabetes, etc.) with the PAM4 assay. (Supported in part by NIH grants CA096924, CA120432 and CA62924, and the Turpin Foundation.)
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2012.30.4_suppl.151
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
    detail.hit.zdb_id: 2005181-5
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  • 6
    Online Resource
    Online Resource
    Effectiveness of Gene Expression Profiling for Response Prediction of Rectal Adenocarcinomas to Preoperative Chemoradiotherapy
    American Society of Clinical Oncology (ASCO) ; 2005
    In:  Journal of Clinical Oncology Vol. 23, No. 9 ( 2005-03-20), p. 1826-1838
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 23, No. 9 ( 2005-03-20), p. 1826-1838
    Abstract: There is a wide spectrum of tumor responsiveness of rectal adenocarcinomas to preoperative chemoradiotherapy ranging from complete response to complete resistance. This study aimed to investigate whether parallel gene expression profiling of the primary tumor can contribute to stratification of patients into groups of responders or nonresponders. Patients and Methods Pretherapeutic biopsies from 30 locally advanced rectal carcinomas were analyzed for gene expression signatures using microarrays. All patients were participants of a phase III clinical trial (CAO/ARO/AIO-94, German Rectal Cancer Trial) and were randomized to receive a preoperative combined-modality therapy including fluorouracil and radiation. Class comparison was used to identify a set of genes that were differentially expressed between responders and nonresponders as measured by T level downsizing and histopathologic tumor regression grading. Results In an initial set of 23 patients, responders and nonresponders showed significantly different expression levels for 54 genes (P 〈 .001). The ability to predict response to therapy using gene expression profiles was rigorously evaluated using leave-one-out cross-validation. Tumor behavior was correctly predicted in 83% of patients (P = .02). Sensitivity (correct prediction of response) was 78%, and specificity (correct prediction of nonresponse) was 86%, with a positive and negative predictive value of 78% and 86%, respectively. Conclusion Our results suggest that pretherapeutic gene expression profiling may assist in response prediction of rectal adenocarcinomas to preoperative chemoradiotherapy. The implementation of gene expression profiles for treatment stratification and clinical management of cancer patients requires validation in large, independent studies, which are now warranted.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2005.00.406
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2005
    detail.hit.zdb_id: 2005181-5
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  • 7
    Online Resource
    Online Resource
    Secondary Cutaneous Vasculitislike MALT Lymphoma With an IGL-MYC Fusion
    American Medical Association (AMA) ; 2009
    In:  Archives of Dermatology Vol. 145, No. 8 ( 2009-08-01)
    Details
    In: Archives of Dermatology, American Medical Association (AMA), Vol. 145, No. 8 ( 2009-08-01)
    Type of Medium: Online Resource
    ISSN: 0003-987X
    URL: Article
    DOI: 10.1001/archdermatol.2009.166
    RVK:
    XA 28900
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2009
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  • 8
    Online Resource
    Online Resource
    The Rectal Cancer microRNAome – microRNA Expression in Rectal Cancer and Matched Normal Mucosa
    American Association for Cancer Research (AACR) ; 2012
    In:  Clinical Cancer Research Vol. 18, No. 18 ( 2012-09-15), p. 4919-4930
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 18, No. 18 ( 2012-09-15), p. 4919-4930
    Abstract: Purpose: miRNAs play a prominent role in a variety of physiologic and pathologic biologic processes, including cancer. For rectal cancers, only limited data are available on miRNA expression profiles, whereas the underlying genomic and transcriptomic aberrations have been firmly established. We therefore, aimed to comprehensively map the miRNA expression patterns of this disease. Experimental Design: Tumor biopsies and corresponding matched mucosa samples were prospectively collected from 57 patients with locally advanced rectal cancers. Total RNA was extracted, and tumor and mucosa miRNA expression profiles were subsequently established for all patients. The expression of selected miRNAs was validated using semi-quantitative real-time PCR. Results: Forty-nine miRNAs were significantly differentially expressed (log2-fold difference & gt;0.5 and P & lt; 0.001) between rectal cancer and normal rectal mucosa. The predicted targets for these miRNAs were enriched for the following pathways: Wnt, TGF-beta, mTOR, insulin, mitogen-activated protein kinase, and ErbB signaling. Thirteen of these 49 miRNAs seem to be rectal cancer-specific, and have not been previously reported for colon cancers: miR-492, miR-542-5p, miR-584, miR-483-5p, miR-144, miR-2110, miR-652, miR-375, miR-147b, miR-148a, miR-190, miR-26a/b, and miR-338-3p. Of clinical impact, miR-135b expression correlated significantly with disease-free and cancer-specific survival in an independent multicenter cohort of 116 patients. Conclusion: This comprehensive analysis of the rectal cancer miRNAome uncovered novel miRNAs and pathways associated with rectal cancer. This information contributes to a detailed view of this disease. Moreover, the identification and validation of miR-135b may help to identify novel molecular targets and pathways for therapeutic exploitation. Clin Cancer Res; 18(18); 4919–30. ©2012 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-12-0016
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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    detail.hit.zdb_id: 2036787-9
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  • 9
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    Abstract 247: A functional genomics and a systems biology approach identify POMP as a potential therapeutic target for colorectal cancer
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 247-247
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 247-247
    Abstract: Colorectal cancer (CRC) is one of the most frequent malignancies in many parts of the world and a leading cause of cancer deaths in both men and women. The identification of rationale therapeutic targets is one possibility to provide personalized medicine to cancer patients. Our approach consisted of identifying overexpressed genes located at sites of recurrent chromosomal amplifications, as these regions are likely to harbor genes required for cancer cell survival. Thirty-one colon cancers and 15 CRC cell lines were analyzed by high-resolution array CGH and microarray gene expression profiling. RNA interference (RNAi)-based analysis identified a subset of genes whose loss-of-function (LOF) reduced the cellular viability of CRC cell lines. Consistent with previous reports, the vast majority of CRC assayed exhibited amplification of the chromosome band 13q12.13-q12.3. Among the genes residing within the 13q12.13-q12.3 amplified region showing an overexpression level of at least two-fold higher in the tumor compared to normal mucosa and whose gene silencing impaired cellular survival, we identified NUPL1, LNX2, POLR1D, CDX2, POMP, and SLC7A1. As little is know of the function of these proteins, we decided to use an unbiased systems biology approach to identify genes, pathways and networks altered following RNAi-mediated LOF of each of these candidate genes. To do this we perturbed the expression of each candidate gene through application of two or more siRNAs corresponding to each gene, followed by whole genome expression profiling to monitor cellular transcriptional responses to gene specific LOF. Concordant gene expression signatures generated using three different RNAi effectors targeting POMP, over a time-course (10, 24, 48, and 72 hours), showed that a decrease in POMP expression of more than 80% at 24 hours initially resulted in only minor downstream changes in gene expression. However, by 48 hours approximately 100 genes exhibited altered expression and by 72 hours nearly 2000 genes. At this last time point a statistically significant enrichment (p & lt;0.05) for the altered expression of genes linked to the gene ontologies of cancer, cell death, and cellular growth was observed. POMP, a proteasome maturation protein, is an essential factor for mammalian proteasome biogenesis. This dynamic loss-of-function approach revealed a regulatory network that controls the transcriptional response of colorectal cancer cells after impairing the function of the proteasome. We are also investigating whether the gene expression profiles observed following silencing of POMP resemble the transcriptomic changes that undergo cells treated with proteasome inhibitors as this may shed further light on the mechanism of action of this new class of anti-cancer drugs particularly in CRC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 247.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-247
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 10
    Online Resource
    Online Resource
    Aneuploidy-Dependent Massive Deregulation of the Cellular Transcriptome and Apparent Divergence of the Wnt/β-catenin Signaling Pathway in Human Rectal Carcinomas
    American Association for Cancer Research (AACR) ; 2006
    In:  Cancer Research Vol. 66, No. 1 ( 2006-01-01), p. 267-282
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 66, No. 1 ( 2006-01-01), p. 267-282
    Abstract: To identify genetic alterations underlying rectal carcinogenesis, we used global gene expression profiling of a series of 17 locally advanced rectal adenocarcinomas and 20 normal rectal mucosa biopsies on oligonucleotide arrays. A total of 351 genes were differentially expressed (P & lt; 1.0e−7) between normal rectal mucosa and rectal carcinomas, 77 genes had a & gt;5-fold difference, and 85 genes always had at least a 2-fold change in all of the matched samples. Twelve genes satisfied all three of these criteria. Altered expression of genes such as PTGS2 (COX-2), WNT1, TGFB1, VEGF, and MYC was confirmed, whereas our data for other genes, like PPARD and LEF1, were inconsistent with previous reports. In addition, we found deregulated expression of many genes whose involvement in rectal carcinogenesis has not been reported. By mapping the genomic imbalances in the tumors using comparative genomic hybridization, we could show that DNA copy number gains of recurrently aneuploid chromosome arms 7p, 8q, 13q, 18q, 20p, and 20q correlated significantly with their average chromosome arm expression profile. Taken together, our results show that both the high-level, significant transcriptional deregulation of specific genes and general modification of the average transcriptional activity of genes residing on aneuploid chromosomes coexist in rectal adenocarcinomas. (Cancer Res 2006; 66(1): 267-82)
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-05-2533
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2006
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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