Profiling immunohistochemical expression of NOTCH1–3, JAGGED1, cMET, and phospho-MAPK in 100 carcinomas of unknown primary

Krikelis, Dimitrios; Pentheroudakis, George; Goussia, Anna; Siozopoulou, Vassiliki; Bobos, Mattheos; Petrakis, Dimitrios; Stoyianni, Aikaterini; Golfinopoulos, Vassilios; Ciuleanu, Tudor-Eliade; Fountzilas, George; Malamou‐Mitsi, Vassiliki; Pavlidis, Nicholas

doi:10.1007/s10585-012-9474-4

Cited by 16 publications

(7 citation statements)

References 32 publications

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“…Given the role of MET in the progression of CUPs, we also evaluated the status of MET in the primary tumor [35, 36]. Analysis of MET revealed no evidence of amplification or other gene alterations (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…Notably, PDCs with neuroendocrine features and gastrointestinal PDCs have shown hyperactivation of the AKT/mTOR pathway [78–82]. Additionally, given the role of MET in the progression of CUPs and the availability of MET-inhibitors in the clinic [35, 36], we evaluated MET status in both the primary patient tumor and PDX tumor models, but found no evidence of genetic or expression abnormalities.…”

Section: Discussionmentioning

confidence: 99%

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A case study of an integrative genomic and experimental therapeutic approach for rare tumors: identification of vulnerabilities in a pediatric poorly differentiated carcinoma

et al. 2016

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BackgroundPrecision medicine approaches are ideally suited for rare tumors where comprehensive characterization may have diagnostic, prognostic, and therapeutic value. We describe the clinical case and molecular characterization of an adolescent with metastatic poorly differentiated carcinoma (PDC). Given the rarity and poor prognosis associated with PDC in children, we utilized genomic analysis and preclinical models to validate oncogenic drivers and identify molecular vulnerabilities.MethodsWe utilized whole exome sequencing (WES) and transcriptome analysis to identify germline and somatic alterations in the patient’s tumor. In silico and in vitro studies were used to determine the functional consequences of genomic alterations. Primary tumor was used to generate a patient-derived xenograft (PDX) model, which was used for in vivo assessment of predicted therapeutic options.ResultsWES revealed a novel germline frameshift variant (p.E1554fs) in APC, establishing a diagnosis of Gardner syndrome, along with a somatic nonsense (p.R790*) APC mutation in the tumor. Somatic mutations in TP53, MAX, BRAF, ROS1, and RPTOR were also identified and transcriptome and immunohistochemical analyses suggested hyperactivation of the Wnt/ß-catenin and AKT/mTOR pathways. In silico and biochemical assays demonstrated that the MAX p.R60Q and BRAF p.K483E mutations were activating mutations, whereas the ROS1 and RPTOR mutations were of lower utility for therapeutic targeting. Utilizing a patient-specific PDX model, we demonstrated in vivo activity of mTOR inhibition with temsirolimus and partial response to inhibition of MEK.ConclusionsThis clinical case illustrates the depth of investigation necessary to fully characterize the functional significance of the breadth of alterations identified through genomic analysis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-016-0366-0) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A case study of an integrative genomic and experimental therapeutic approach for rare tumors: identification of vulnerabilities in a pediatric poorly differentiated carcinoma

et al. 2016

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“…The immunostained results of Notch-1 protein were semi-quantitated according to the criteria from published literatures [2,11]. Each section randomly selected 5 high-power fields, positive cells represented by the percentage of totally number of similar cells.…”

Section: Methodsmentioning

confidence: 99%

Expression of Notch-1 and its clinical significance in different histological subtypes of human lung adenocarcinoma

Huang

Song

Liu

et al. 2013

J Exp Clin Cancer Res

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BackgroundAccording to the International Multidisciplinary Classification of Lung Adenocarcinoma (LAD) by International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) in 2011, the diagnosis of LAD is changing from simple morphology into a comprehensive multidisciplinary classification. The aim of this study is to detect the expression of Notch-1 and analyze its clinicopathological or prognostic significance in different histological subtypes of Lung Adenocarcinomas (LADs).MethodsWestern blot and Semi-quantitative Reverse transcription-polymerase chain reaction (RT-PCR) assays, as well as immunohisitochemistry, were performed to detect the expression of Notch-1 in LAD cells and tissue samples. Kaplan-Meier and multivariate Cox regression analyses were performed to evaluate the correlation of Notch-1 expression with clinicopathological factors and prognosis of LAD patients.ResultsThe expression level of Notch-1 protein in LAD cell lines or tissues was significantly lower than that in normal human bronchial epithelial cell line (16HBE) or nontumor tissues (P < 0.05). By statistical analyses, it was observed that negative Notch-1 expression was significantly associated with advanced clinical stage (P = 0.001) and lymph node metastasis (P = 0.026) in LAD patients. Also, the recurrence rate of Notch-1-positive group was higher than the Notch-1-negative group (P = 0.001), and patients with positive Notch-1 expression have a prolonged progression of overall survival (P = 0.033). More interestingly, the expression of Notch-1 protein was often observed to be negative in solid predominant adenocarcinoma (SPA) tissues, but highly expressed in papillary predominant adenocarcinoma (PPA) and micropapillary predominant adenocarcinoma (MPA) tissues. Kaplan-Meier survival analysis showed that patients with positive Notch-1 expression had a prolonged progression of overall survival compared with those with negative Notch-1 expression (P = 0.033). The median survival time of Notch-1-positive or negative patients was 64.6 months (95% CI: 31.497-97.703 months) or 36.0 months (95% CI: 12.132-59.868 months).ConclusionsNotch-1 could be used as a predictable biomarker to be detected in different pathological and histological subtypes in LAD for diagnosis or prognosis.

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“…The immunohistochemistrical antibodies were listed as follows: CD10 (56C6, Dako), Bcl6 (M7211, Dako), MUM1 (MUM1p, Dako), Ki67 (MB1, Dako), P50 (sc-8414, Santa Cruz), P65 (#4764, Cell Signaling) and Notch2 (ab52302, Abcam). For Ki67 [26] and Notch2 [27] , cases were considered to be positive when 25% or 20% of lymphoma cells were stained, respectively. For the rest antibodies, we defined 30% as the cut-off [28] , [29] .…”

Section: Methodsmentioning

confidence: 99%

The Truncate Mutation of Notch2 Enhances Cell Proliferation through Activating the NF-κB Signal Pathway in the Diffuse Large B-Cell Lymphomas

et al. 2014

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The Notch2 is a critical membrane receptor for B-cell functions, and also displays various biological roles in lymphoma pathogenesis. In this article, we reported that 3 of 69 (4.3%) diffuse large B-cell lymphomas (DLBCLs) exhibited a truncate NOTCH2 mutation at the nucleotide 7605 (G/A) in the cDNA sequence, which led to partial deletion of the C-terminal of PEST (proline-, glutamic acid-, serine- and threonine-rich) domain. The truncate Notch2 activated both the Notch2 and the NF-κB signals and promoted the proliferation of B-cell lymphoma cell lines, including DLBCL and Burkitt's lymphoma cell lines. Moreover, the ectopic proliferation was completely inhibited by ammonium pyrrolidinedithiocarbamate (PDTC), an NF-κB inhibitor. Simultaneously, PDTC also reduced the expression level of Notch2. Based on these results, we conclude that the Notch2 receptor with PEST domain truncation enhances cell proliferation which may be associated with the activation of the Notch2 and the NF-κB signaling. Our results are expected to provide a possible target for new DLBCL therapies by suppressing the Notch2 and the NF-κB signaling.

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Profiling immunohistochemical expression of NOTCH1–3, JAGGED1, cMET, and phospho-MAPK in 100 carcinomas of unknown primary

Cited by 16 publications

References 32 publications

A case study of an integrative genomic and experimental therapeutic approach for rare tumors: identification of vulnerabilities in a pediatric poorly differentiated carcinoma

A case study of an integrative genomic and experimental therapeutic approach for rare tumors: identification of vulnerabilities in a pediatric poorly differentiated carcinoma

Expression of Notch-1 and its clinical significance in different histological subtypes of human lung adenocarcinoma

The Truncate Mutation of Notch2 Enhances Cell Proliferation through Activating the NF-κB Signal Pathway in the Diffuse Large B-Cell Lymphomas

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