Src pathway activation in RCC and the correlation with grade and survival and the development of a rational new target in RCC.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 453-453
Author(s):  
Chung-Han Lee ◽  
Martin Henner Voss ◽  
Roy Mano ◽  
Robert John Motzer ◽  
James Hsieh
Keyword(s):  
Overall Survival ◽  
Mrna Expression ◽  
Cell Lines ◽  
Survival Data ◽  
Therapeutic Potential ◽  
The Cancer Genome Atlas ◽  
Primary Tumors ◽  
Fuhrman Grade ◽  
Inhibitory Site ◽  
Src Pathway

453 Background: Loss of the VHL tumor suppressor in clear cell renal cell carcinoma (ccRCC) leads to the accumulation of Hypoxia Inducible Factor (HIF) and aberrant transcription of downstream targets such as VEGF. Inhibition of VEGF is the underlying therapeutic principle of several approved targeted agents; however, other HIF transcriptional targets remain to be explored. Increased expression of the HIF transcriptional target CUB domain-containing protein 1 (CDCP1) is associated with poor survival in ccRCC. CDCP1 is a substrate and binding partner for Src-family tyrosine kinases (SFKs) and dictates substrate specificity. Crosstalk between the SFK signaling cascade and the HIF pathway may result in feed forward signal amplification. Upregulation of Src signaling increases HIF-dependent transcription by both VHL-dependent and -independent mechanisms. Reciprocally, HIF accumulation can activate Src through PDGFRα, focal adhesion kinase, and CDCP1. Methods: Data from The Cancer Genome Atlas (TCGA) was used to assess mRNA expression and protein phosphorylation as well as clinical parameters and outcome in patients with ccRCC. Correlations were analyzed via Mann-Whitney U-test. Survival data was obtained using the TCGA portal, and analyzed by logrank test. To investigate the therapeutic potential of Src inhibition, the IC50 of Dasatinib in primary tumors derived cell lines were determined by an AlamarBlue Assay. Results: Increased Src and CDCP1 mRNA expression and decreased phosphorylation on the Src inhibitory site Y527 correlated with increased Fuhrman grade. Decreased phosphorylation on the inhibitory site Y527 correlated with worse median overall survival (78.4 vs. 19.7 months, p< 0.00001). Similarly, increased Src and CDCP1 mRNA expression correlated with worse overall survival (78.4 vs. 26.9 months, p < 0.00001, 78.4 vs. 37.2 months, p = 0.005). In vitro inhibition of Src with Dasatinib induces growth inhibition of primary cell lines with sarcomatoid or rhabdoid features, histomorphologic criteria associated with higher grade disease and worse prognosis. Conclusions: The Src pathway might be biologically relevant for ccRCC, and Src inhibition may have therapeutic potential.

scholarly journals Monosomy 3 Is Linked to Resistance to MEK Inhibitors in Uveal Melanoma

2021 ◽  
Vol 22 (13) ◽  
pp. 6727
Author(s):  
Svenja Mergener ◽  
Jens T. Siveke ◽  
Samuel Peña-Llopis
Keyword(s):  
Cell Lines ◽  
Uveal Melanoma ◽  
Survival Data ◽  
Translation Initiation Factor ◽  
The Cancer Genome Atlas ◽  
Initiation Factor ◽  
Chromosome 3 ◽  
Mek Inhibitors ◽  
Mek Inhibition ◽  
Insight Into

The use of MEK inhibitors in the therapy of uveal melanoma (UM) has been investigated widely but has failed to show benefits in clinical trials due to fast acquisition of resistance. In this study, we investigated a variety of therapeutic compounds in primary-derived uveal melanoma cell lines and found monosomy of chromosome 3 (M3) and mutations in BAP1 to be associated with higher resistance to MEK inhibition. However, reconstitution of BAP1 in a BAP1-deficient UM cell line was unable to restore sensitivity to MEK inhibition. We then compared UM tumors from The Cancer Genome Atlas (TCGA) with mutations in BAP1 with tumors with wild-type BAP1. Principal component analysis (PCA) clearly differentiated both groups of tumors, which displayed disparate overall and progression-free survival data. Further analysis provided insight into differential expression of genes involved in signaling pathways, suggesting that the downregulation of the eukaryotic translation initiation factor 2A (EIF2A) observed in UM tumors with BAP1 mutations and M3 UM cell lines might lead to a decrease in ribosome biogenesis while inducing an adaptive response to stress. Taken together, our study links loss of chromosome 3 with decreased sensitivity to MEK inhibition and gives insight into possible related mechanisms, whose understanding is fundamental to overcome resistance in this aggressive tumor.

scholarly journals Predicted CD4+ T cell infiltration levels could indicate better overall survival in sarcoma patients

2021 ◽  
Vol 49 (1) ◽  
pp. 030006052098153
Author(s):  
Qing Bi ◽  
Yang Liu ◽  
Tao Yuan ◽  
Huizhen Wang ◽  
Bin Li ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Survival Data ◽  
Tumor Infiltrating Lymphocytes ◽  
The Cancer Genome Atlas ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Whole Exome ◽  
Cancer Genome Atlas ◽  
Infiltrating Lymphocytes

Objective The role of tumor-infiltrating lymphocytes (TILs) has not yet been characterized in sarcomas. The aim of this bioinformatics study was to explore the effect of TILs on sarcoma survival and genome alterations. Methods Whole-exome sequencing, transcriptome sequencing, and survival data of sarcoma were obtained from The Cancer Genome Atlas. Immune infiltration scores were calculated using the Tumor Immune Estimation Resource. Potential associations between abundance of infiltrating TILs and survival or genome alterations were examined. Results Levels of CD4+ T cell infiltration were associated with overall survival of patients with pan-sarcomas, and higher CD4+ T cell infiltration levels were associated with better survival. Somatic copy number alterations, rather than mutations, were found to correlate with CD4+ T cell infiltration levels. Conclusions This data mining study indicated that CD4+ T cell infiltration levels predicted from RNA sequencing could predict sarcoma prognosis, and higher levels of CD4+ T cells infiltration indicated a better chance of survival.

scholarly journals Heme Biosynthesis mRNA Expression Signature: Towards a Novel Prognostic Biomarker in Patients with Diffusely Infiltrating Gliomas

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 662
Author(s):  
Mario Mischkulnig ◽  
Barbara Kiesel ◽  
Daniela Lötsch ◽  
Thomas Roetzer ◽  
Martin Borkovec ◽  
...  
Keyword(s):  
Overall Survival ◽  
Mrna Expression ◽  
Postoperative Management ◽  
Heme Biosynthesis ◽  
The Cancer Genome Atlas ◽  
Sequencing Data ◽  
Who Grade ◽  
Expression Signature ◽  
Cancer Genome Atlas ◽  
The Impact

Diffusely infiltrating gliomas are characterized by a variable clinical course, and thus novel prognostic biomarkers are needed. The heme biosynthesis cycle constitutes a fundamental metabolic pathway and might play a crucial role in glioma biology. The aim of this study was thus to investigate the role of the heme biosynthesis mRNA expression signature on prognosis in a large glioma patient cohort. Glioma patients with available sequencing data on heme biosynthesis expression were retrieved from The Cancer Genome Atlas (TCGA). In each patient, the heme biosynthesis mRNA expression signature was calculated and categorized into low, medium, and high expression subgroups. Differences in progression-free and overall survival between these subgroups were investigated including a multivariate analysis correcting for WHO grade, tumor subtype, and patient age and sex. In a total of 693 patients, progression-free and overall survival showed a strictly monotonical decrease with increasing mRNA expression signature subgroups. In detail, median overall survival was 134.2 months in the low, 79.9 months in the intermediate, and 16.5 months in the high mRNA expression signature subgroups, respectively. The impact of mRNA expression signature on progression-free and overall survival was independent of the other analyzed prognostic factors. Our data indicate that the heme biosynthesis mRNA expression signature might serve as an additional novel prognostic marker in patients with diffusely infiltrating gliomas to optimize postoperative management.

scholarly journals Eps15 Homology Domain-Containing Protein 3 Hypermethylation as a Prognostic and Predictive Marker for Colorectal Cancer

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 453
Author(s):  
Yu-Han Wang ◽  
Shih-Ching Chang ◽  
Muhamad Ansar ◽  
Chin-Sheng Hung ◽  
Ruo-Kai Lin
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Mrna Expression ◽  
Proportional Hazards ◽  
Uterine Cancer ◽  
Colonic Polyps ◽  
Predictive Marker ◽  
Cox Proportional Hazards ◽  
The Cancer Genome Atlas ◽  
Eps15 Homology Domain

Colorectal cancer (CRC) arises from chromosomal instability, resulting from aberrant hypermethylation in tumor suppressor genes. This study identified hypermethylated genes in CRC and investigated how they affect clinical outcomes. Methylation levels of specific genes were analyzed from The Cancer Genome Atlas dataset and 20 breast cancer, 16 esophageal cancer, 33 lung cancer, 15 uterine cancer, 504 CRC, and 9 colon polyp tissues and 102 CRC plasma samples from a Taiwanese cohort. In the Asian cohort, Eps15 homology domain-containing protein 3 (EHD3) had twofold higher methylation in 44.4% of patients with colonic polyps, 37.3% of plasma from CRC patients, and 72.6% of CRC tissues, which was connected to vascular invasion and high microsatellite instability. Furthermore, EHD3 hypermethylation was detected in other gastrointestinal cancers. In the Asian CRC cohort, low EHD3 mRNA expression was found in 45.1% of patients and was connected to lymph node metastasis. Multivariate Cox proportional-hazards survival analysis revealed that hypermethylation in women and low mRNA expression were associated with overall survival. In the Western CRC cohort, EHD3 hypermethylation was also connected to overall survival and lower chemotherapy and antimetabolite response rates. In conclusion, EHD3 hypermethylation contributes to the development of CRC in both Asian and Western populations.

scholarly journals Increased GOLM1 Expression Independently Predicts Unfavorable Overall Survival and Recurrence-Free Survival in Lung Adenocarcinoma

2018 ◽  
Vol 25 (1) ◽  
pp. 107327481877800 ◽  
Author(s):  
Xi Liu ◽  
Lei Chen ◽  
Tao Zhang
Keyword(s):  
Overall Survival ◽  
Lung Adenocarcinoma ◽  
Survival Data ◽  
Methylation Status ◽  
Lung Squamous Cell Carcinoma ◽  
Prognostic Indicator ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Recurrence Free Survival ◽  
Free Survival

Golgi membrane protein 1 (GOLM1) is a transmembrane glycoprotein of the Golgi cisternae, which is implicated in carcinogenesis of multiple types of cancer. In this study, using data from the Gene Expression Omnibus and The Cancer Genome Atlas, we compared the expression of GOLM1 in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) and studied its prognostic value in terms of overall survival (OS) and recurrence-free survival (RFS) in these 2 subtypes of non-small cell lung cancer (NSCLC). Results showed that GOLM1 was significantly upregulated in both LUAD and LUSC tissues compared to the normal controls. However, GOLM1 expression was higher in LUAD tissues than in LUSC tissues. More importantly, using over 10 years’ survival data from 502 patients with LUAD and 494 patients with LUSC, we found that high GOLM1 expression was associated with unfavorable OS and RFS in patients with LUAD, but not in patients with LUSC. The following univariate and multivariate analyses confirmed that increased GOLM1 expression was an independent prognostic indicator of poor OS (hazard ratio [HR]: 1.30, 95% confidence interval [CI]: 1.11-1.54, P = .002) and RFS (HR: 1.37, 95% CI: 1.14-1.64, P = .001) in patients with LUAD. Of 511 cases with LUAD, 248 (48.5%) had heterozygous loss (−1), while 28 (5.5%) of 511 cases with LUAD had low-level copy gain (+1). In addition, we also found that the methylation status of 1 CpG site (chr9: 88,694,942-88,694,944) showed a weak negative correlation with GOLM1 expression (Pearson r = −0.25). Based on these findings, we infer that GOLM1 might serve as a valuable prognostic biomarker in LUAD, but not in LUSC. In addition, DNA copy number alterations and methylation might be 2 important mechanisms of dysregulated GOLM1 in LUAD.

scholarly journals High Cysteinyl Leukotriene Receptor 1 Expression Correlates with Poor Survival of Uveal Melanoma Patients and Cognate Antagonist Drugs Modulate the Growth, Cancer Secretome, and Metabolism of Uveal Melanoma Cells

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2950
Author(s):  
Kayleigh Slater ◽  
Aisling B. Heeran ◽  
Sandra Garcia-Mulero ◽  
Helen Kalirai ◽  
Rebeca Sanz-Pamplona ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cell Lines ◽  
Uveal Melanoma ◽  
Therapeutic Potential ◽  
Unmet Need ◽  
Digital Pathology ◽  
Disease Free Survival ◽  
High Expression ◽  
Poor Overall Survival ◽  
Cysteinyl Leukotriene

Metastatic uveal melanoma (UM) is a rare, but often lethal, form of ocular cancer arising from melanocytes within the uveal tract. UM has a high propensity to spread hematogenously to the liver, with up to 50% of patients developing liver metastases. Unfortunately, once liver metastasis occurs, patient prognosis is extremely poor with as few as 8% of patients surviving beyond two years. There are no standard-of-care therapies available for the treatment of metastatic UM, hence it is a clinical area of urgent unmet need. Here, the clinical relevance and therapeutic potential of cysteinyl leukotriene receptors (CysLT1 and CysLT2) in UM was evaluated. High expression of CYSLTR1 or CYSLTR2 transcripts is significantly associated with poor disease-free survival and poor overall survival in UM patients. Digital pathology analysis identified that high expression of CysLT1 in primary UM is associated with reduced disease-specific survival (p = 0.012; HR 2.76; 95% CI 1.21–6.3) and overall survival (p = 0.011; HR 1.46; 95% CI 0.67–3.17). High CysLT1 expression shows a statistically significant (p = 0.041) correlation with ciliary body involvement, a poor prognostic indicator in UM. Small molecule drugs targeting CysLT1 were vastly superior at exerting anti-cancer phenotypes in UM cell lines and zebrafish xenografts than drugs targeting CysLT2. Quininib, a selective CysLT1 antagonist, significantly inhibits survival (p < 0.0001), long-term proliferation (p < 0.0001), and oxidative phosphorylation (p < 0.001), but not glycolysis, in primary and metastatic UM cell lines. Quininib exerts opposing effects on the secretion of inflammatory markers in primary versus metastatic UM cell lines. Quininib significantly downregulated IL-2 and IL-6 in Mel285 cells (p < 0.05) but significantly upregulated IL-10, IL-1β, IL-2 (p < 0.0001), IL-13, IL-8 (p < 0.001), IL-12p70 and IL-6 (p < 0.05) in OMM2.5 cells. Finally, quininib significantly inhibits tumour growth in orthotopic zebrafish xenograft models of UM. These preclinical data suggest that antagonism of CysLT1, but not CysLT2, may be of therapeutic interest in the treatment of UM.

scholarly journals Differential expression of FXYD1 in cancers of the breast.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Differential Expression ◽  
Survival Data ◽  
Molecular Subtype ◽  
Normal Breast ◽  
Luminal A ◽  
Significant Differential Expression ◽  
Primary Tumors ◽  
Tumor Expression

Breast cancer affects women at relatively high frequency (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding FXYD domain containing ion transport regulator 1, FXYD1, when comparing primary tumors of the breast to the tissue of origin, the normal breast. FXYD1 mRNA was present at significantly reduced quantity in tumors of the breast as compared to normal breast tissue. Analysis of human survival data revealed that expression of FXYD1 in primary tumors of the breast was correlated with overall survival in patients with basal and luminal A subtype cancers, demonstrating a relationship between correlation of primary tumor expression with overall survival based on molecular subtype. FXYD1 may be of relevance to initiation, maintenance or progression of cancers of the female breast.

scholarly journals Differential expression of M-phase phosphoprotein 9 in cancers of the breast.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Differential Expression ◽  
Survival Data ◽  
Molecular Subtype ◽  
Normal Breast ◽  
Differentially Expressed ◽  
Significant Differential Expression ◽  
Primary Tumors ◽  
M Phase

Breast cancer affects women at relatively high frequency (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding the M-phase phosphoprotein 9, MPHOSPH9, when comparing primary tumors of the breast to the tissue of origin, the normal breast. MPHOSPH9 was also differentially expressed in the tumor cells of patients with triple negative breast cancer. MPHOSPH9 mRNA was present at significantly higher quantities in tumors of the breast as compared to normal breast tissue. Analysis of human survival data revealed that expression of MPHOSPH9 in primary tumors of the breast was correlated with overall survival in patients with luminal A subtype cancer, demonstrating a relationship between correlation of primary tumor expression with overall survival based on molecular subtype. MPHOSPH9 may be of relevance to initiation, maintenance or progression of cancers of the female breast.

scholarly journals Restoring HOXD10 Exhibits Therapeutic Potential for Ameliorating Malignant Progression and 5-Fluorouracil Resistance in Colorectal Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Weijie Pan ◽  
Kaijing Wang ◽  
Jiayong Li ◽  
Hanhua Li ◽  
Yuchan Cai ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Therapeutic Potential ◽  
Methylation Status ◽  
Suppressor Gene ◽  
Resistant Cell ◽  
The Cancer Genome Atlas ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Normal Tissues

Emerging evidence suggests that hypermethylation of HOXD10 plays an important role in human cancers. However, the biological and clinical impacts of HOXD10 overmethylation and its downstream targets in colorectal cancer remain unknown. We evaluated the methylation level of HOXD10 in paired cancer and normal tissues (n = 42) by using pyrosequencing, followed by validation of the methylation status of HOXD10 from The Cancer Genome Atlas (TCGA) datasets with 302 cancer tissues and 38 normal tissues. The biological function of HOXD10 was characterized in cell lines. We further evaluated the effects of HOXD10 and its targets on chemoresistance in our established resistant cell lines and clinical cohort (n = 66). HOXD10 was found frequently methylated in colorectal cancer, and its hypermethylation correlates with its low expression level, advanced disease, and lymph node metastasis. Functionally, HOXD10 acts as a tumor suppressor gene, in which HOXD10-expressing cells showed suppressed cell proliferation, colony formation ability, and migration and invasion capacity. Mechanistically, DNMT1, DNMT3B, and MeCP2 were recruited in the HOXD10 promoter, and demethylation by 5-Aza-2′-deoxycytidine (5-Aza-CdR) treatment or MeCP2 knockdown can sufficiently induce HOXD10 expression. HOXD10 regulates the expressions of miR-7 and IGFBP3 in a promoter-dependent manner. Restoration of the expression of HOXD10 in 5-fluorouracil (5-FU)-resistant cells significantly upregulates the expressions of miR-7 and IGFBP3 and enhances chemosensitivity to 5-FU. In conclusion, we provide novel evidence that HOXD10 is frequently methylated, silenced, and contributes to the development of colorectal cancers. Restoration of HOXD10 activates the expressions of miR-7 and IGFBP3 and results in an inhibited phenotype biologically, suggesting its potential therapeutic relevance in colorectal cancer (CRC).

scholarly journals Differential expression of sprouty RTK signaling antagonist 2 in cancers of the breast.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Differential Expression ◽  
Survival Data ◽  
Molecular Subtype ◽  
Normal Breast ◽  
Luminal A ◽  
Significant Differential Expression ◽  
Primary Tumors ◽  
Rtk Signaling

Breast cancer affects women at relatively high frequency (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding sprouty RTK signaling antagonist 2, SPRY2, when comparing primary tumors of the breast to the tissue of origin, the normal breast. SPRY2 mRNA was present at significantly reduced quantity in tumors of the breast as compared to normal breast tissue. Analysis of human survival data revealed that expression of SPRY2 in primary tumors of the breast was correlated with overall survival in patients with basal and luminal A subtype cancers, demonstrating a relationship between correlation of primary tumor expression with overall survival based on molecular subtype. SPRY2 may be of relevance to initiation, maintenance or progression of cancers of the female breast.

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