scholarly journals Functional genomics identifies AMPD2 as a new prognostic marker for undifferentiated pleomorphic sarcoma

2018 ◽  
Author(s):  
Martin F. Orth ◽  
Julia S. Gerke ◽  
Thomas Knösel ◽  
Annelore Altendorf-Hofmann ◽  
Julian Musa ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prognostic Marker ◽  
Survival Data ◽  
Copy Number ◽  
Small Sample ◽  
Omics Data ◽  
Primary Tumors ◽  
Undifferentiated Pleomorphic Sarcoma ◽  
Pleomorphic Sarcoma ◽  
Novel Biomarkers

ABSTRACTSoft-tissue sarcomas are rare, heterogeneous and often aggressive mesenchymal cancers. Many of them are associated with poor outcome, in part because biomarkers that can reliably identify high-risk patients are lacking. Studies on sarcomas often are limited by small sample sizes rendering the identification of novel biomarkers difficult when focusing only on individual cohorts. However, the increasing number of publicly available ‘omics’ data opens inroads to overcome this obstacle.Here, we combine high-throughput transcriptome analyses, immunohistochemistry, and functional assays to show that high adenosine monophosphate deaminase 2 (AMPD2) is a robust prognostic biomarker for worse patient outcome in undifferentiated pleomorphic sarcoma (UPS). Publicly available gene expression and survival data for UPS from two independent studies, The Cancer Genome Atlas (TCGA) and the CINSARC reference dataset, were subjected to survival association testing. Genes, whose high expression was significantly correlated with worse outcome in both cohorts (overall and metastasis-free survival), were considered as prognostic marker candidates. The best candidate, AMPD2, was validated on protein level in an independent tissue microarray. Analysis of DNA copy-number and matched gene expression data indicated that high AMPD2 expression is significantly correlated with copy-number gains at the AMPD2 locus. Gene-set enrichment analyses of AMPD2 co-expressed genes in both UPS gene expression datasets suggested that highly AMPD2 expressing tumors are enriched in gene signatures involved in tumorigenesis. Consistent with this prediction in primary tumors, knockdown of AMPD2 by RNA interference with pooled siRNAs or a doxycycline-inducible shRNA construct in the UPS cell line FPS-1 markedly inhibited proliferation in vitro and tumorigenicity in vivo.Collectively, these results provide evidence that AMPD2 may serve as a novel biomarker for outcome prediction in UPS. Our study exemplifies how the integration of available ‘omics’ data, immunohistochemical analyses, and functional experiments can identify novel biomarkers even in a rare sarcoma, which may serve as a blueprint for biomarker identification for other rare cancers.

scholarly journals Functional genomics identifies AMPD2 as a new prognostic marker for undifferentiated pleomorphic sarcoma

2018 ◽  
Vol 144 (4) ◽  
pp. 859-867 ◽  
Author(s):  
Martin F. Orth ◽  
Julia S. Gerke ◽  
Thomas Knösel ◽  
Annelore Altendorf-Hofmann ◽  
Julian Musa ◽  
...  
Keyword(s):  
Functional Genomics ◽  
Prognostic Marker ◽  
Undifferentiated Pleomorphic Sarcoma ◽  
Pleomorphic Sarcoma

scholarly journals Copy number gain of CMTM6 increases the expression of PD-L1 in undifferentiated pleomorphic sarcoma

2021 ◽  
Author(s):  
Shin Ishihara ◽  
Takeshi Iwasaki ◽  
Kenichi Kohashi ◽  
Yuichi Yamada ◽  
Yu Toda ◽  
...  
Keyword(s):  
Copy Number ◽  
Transmembrane Domain ◽  
Gene Copy Number ◽  
Copy Number Gain ◽  
The Cancer Genome Atlas ◽  
Gene Copy ◽  
Undifferentiated Pleomorphic Sarcoma ◽  
Pleomorphic Sarcoma ◽  
Number Variation ◽  
Cancer Genome Atlas

Abstract Background Undifferentiated pleomorphic sarcoma (UPS) is a sarcoma with a poor prognosis. A clinical trial, SARC028, revealed that treatment with anti-PD-1 drugs was effective against UPS. Studies have reported that UPS expresses PD-L1, sometime strongly (≥ 50%). However, the mechanism of PD-L1 expression in UPS has remained still unclear. CKLF-like MARVEL transmembrane domain containing 6 (CMTM6) was identified as a novel regulator of PD-L1 expression. The positive relationship between PD-L1 and CMTM6 has been reported in several studies. The aim of this study was to examine CMTM6 expression in UPS and evaluate the relationship between PD-L1 and CMTM6. Materials and methods Fifty-one primary UPS samples were subjected to CMTM6 and PD-L1 immunostaining. CMTM6 expression was assessed using proportion and intensity scores. CMTM6 gene copy number was also evaluated using a real-time PCR-based copy number assay. We also analyzed the mRNA expression and copy number variation of PD-L1 and CMTM6 in The Cancer Genome Atlas (TCGA) data. Results TCGA data indicated that the mRNAs encoded by genes located around 3p22 were coexpressed with CMTM6 mRNA in UPS. Both proportion and intensity scores of CMTM6 positively correlated with strong PD-L1 expression (≥ 50%) (both p = 0.023). CMTM6 copy number gain increased CMTM6 expression. Patients with UPS with a high CMTM6 intensity score had worse prognosis for overall survival. Conclusions CMTM6 expression was significantly correlated with PD-L1 expression. CMTM6 expression induced strong PD-L1 expression (≥ 50%). CMTM6 copy number gain promoted CMTM6 expression and increased PD-L1 expression in UPS.

scholarly journals Linking genotype to phenotype in multi-omics data of small sample

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Xinpeng Guo ◽  
Yafei Song ◽  
Shuhui Liu ◽  
Meihong Gao ◽  
Yang Qi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Data ◽  
Gene Clusters ◽  
Small Sample ◽  
Large Sample Size ◽  
Genome Wide Association Studies ◽  
Omics Data ◽  
Expression Data ◽  
Large Sample ◽  
Sample Set

Abstract Background Genome-wide association studies (GWAS) that link genotype to phenotype represent an effective means to associate an individual genetic background with a disease or trait. However, single-omics data only provide limited information on biological mechanisms, and it is necessary to improve the accuracy for predicting the biological association between genotype and phenotype by integrating multi-omics data. Typically, gene expression data are integrated to analyze the effect of single nucleotide polymorphisms (SNPs) on phenotype. Such multi-omics data integration mainly follows two approaches: multi-staged analysis and meta-dimensional analysis, which respectively ignore intra-omics and inter-omics associations. Moreover, both approaches require omics data from a single sample set, and the large feature set of SNPs necessitates a large sample size for model establishment, but it is difficult to obtain multi-omics data from a single, large sample set. Results To address this problem, we propose a method of genotype-phenotype association based on multi-omics data from small samples. The workflow of this method includes clustering genes using a protein-protein interaction network and gene expression data, screening gene clusters with group lasso, obtaining SNP clusters corresponding to the selected gene clusters through expression quantitative trait locus data, integrating SNP clusters and corresponding gene clusters and phenotypes into three-layer network blocks, analyzing and predicting based on each block, and obtaining the final prediction by taking the average. Conclusions We compare this method to others using two datasets and find that our method shows better results in both cases. Our method can effectively solve the prediction problem in multi-omics data of small sample, and provide valuable resources for further studies on the fusion of more omics data.

Markers of sunitinib-resistance in clear cell renal cell carcinoma: A gene expression analysis.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 533-533
Author(s):  
Òscar Reig ◽  
Mercedes Marín-Aguilera ◽  
Juan José Lozano ◽  
Blanca Gonzalez ◽  
Carme Mallofré ◽  
...  
Keyword(s):  
Gene Expression ◽  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Expression Analysis ◽  
Renal Cell ◽  
Gene Expression Analysis ◽  
Predictive Biomarkers ◽  
Intrinsic Resistance ◽  
Primary Tumors ◽  
Novel Biomarkers

533 Background: Sunitinib is a standard first line treatment of metastatic renal cell carcinoma (ccRCC). Approximately 20% of patients experience primary resistance to therapy and no predictive biomarkers are available. The aim of our study is to discover novel biomarkers to predict response to sunitinib and to generate hypothesis about mechanisms of intrinsic resistance. Methods: Gene expression analysis was performed in formalin-fixed paraffin embedded (FFPE) samples from 44 patients with metastatic ccRCC treated with sunitinib in our institution. Affymetrix Human Gene 2.0 ST array was performed in primary tumors from 6 extremely sensitive (progression free survival (PFS) > 24 months) and 8 refractory (progression disease as best response) ccRCC. Technical validation with qPCR (Fluidigm Dynamic 96.96 Array) was performed in the whole cohort. The ΔΔCt method was used to quantify the relative amount of mRNA. Clinical and pathological data were correlated with gene expression. Results: 330 genes were differentially expressed between refractory and sensitive patients (p≤0.05). Network analysis showed 16 significant networks represented. Gene expression of 96 selected markers was tested in 47 primary tumors and 24 metastases. We found IL8, VEGF and NOTCH pathways upregulated on refractory patients. Survival analysis showed that the overexpression of IL8 correlated with a worse PFS (HR: 2.42, 95%CI1.27 – 4.63, p=0.0075) and overall survival (OS) (HR: 3.42, 95%CI 1.50 – 7.79, p=0.0034). Overexpression of VEGFBcorrelated with a prolonged PFS (HR 0.52, 95% CI 0.28 – 0.98, p=0.0415). Conclusions: Our results confirm the predictive value of IL8 expression in a cohort of ccRCC patients treated with sunitinib and suggests novel biomarkers of response to sunitinib. These data will be further validated in an independent cohort of patients.

Insulin-like growth factor receptor 1 (IGF1R) protein expression, mRNA expression and gene copy number in operable non-small cell lung cancer (NSCLC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7524-7524
Author(s):  
R. Dziadziuszko ◽  
D. T. Merrick ◽  
S. E. Witta ◽  
A. D. Mendoza ◽  
B. Szostakiewicz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Expression ◽  
Mrna Expression ◽  
Gene Amplification ◽  
Copy Number ◽  
Gene Copy Number ◽  
Inverse Correlation ◽  
Large Cell ◽  
Gene Copy ◽  
Primary Tumors

7524 Background: IGF1R is a promising target for NSCLC therapy. We have evaluated IGF1R protein expression, mRNA expression and gene copy number in primary tumors from surgically treated NSCLC patients (pts) as a reference for correlative biomarker studies in trials using IGF1R inhibitors. Methods: The study included 189 consecutive NSCLC pts who underwent curative pulmonary resection. There were 24% females, 54% squamous cell carcinomas (SCC), 29% adenocarcinomas (AC), 3% large cell carcinomas, 14% other histologies; p stage I: 41%, pII: 22%, pIII: 32% and pIV: 4%. IGF1R expression was evaluated in tissue microarrays by immunohistochemistry (IHC) with Ventana CONFIRM (N=179) and Novus (#NB600–559) anti-IGF1R Ab scored by two observers (H score 0–400). IGF1R gene copy number was assessed by FISH using customized probes (N=181). IGF1R gene expression was evaluated using qRT-PCR from 114 corresponding fresh-frozen samples. Results: Patterns of IHC staining were different for the Ventana and the Novus Ab (inverse correlation, r=-0.16, p=0.04, N=177). IGF1R protein expression detected by Ventana Ab (> median score) was more frequent in SCC (76%) than AC and other histologies (14%, p<0.001) and in pts with higher stage (p=0.03) but was not associated with survival (p=0.46). IGF1R H score by Ventana Ab, but not by Novus Ab, correlated with mRNA expression (r=0.37, p<0.001). IGF1R mRNA expression tended to be higher in SCC than in other histologies (p=0.089), but did not associate with other clinical features or survival (p=0.73). According to criteria previously established for EGFR, IGF1R gene copy number by FISH showed 5 tumors with gene amplification (2.8%), 43 tumors - high polysomy (23.8%), 87 tumors - low polysomy (48.1%), and 46 tumors - trisomy/disomy (25.4%). Pts with gene amplification/high polysomy had 3-yr survival of 60% (95% CI 47% - 74%) vs. 48% (38% - 59%) for low polysomy and 35% (21% - 49%) for trisomy/disomy pts (p=0.016). Prognostic value of IGF1R gene copy number was confirmed in the multivariate analysis. Conclusions: IGF1R protein expression is higher in SCC. IGF1R protein and gene expression does not associate with survival, whereas high IGF1R gene copy number associates with better prognosis in operable NSCLC. [Table: see text]

scholarly journals NLRP12 is differentially expressed and up-regulated in the bone metastases of patients with metastatic breast cancer.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Lymph Node ◽  
Lymph Nodes ◽  
Survival Data ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Metastatic Breast ◽  
Immune Gene ◽  
Primary Tumors

To understand the transcriptional nature of metastasis to disparate sites in human breast cancer, we mined published microarray data (1), comparing global gene expression profiles of metastasis to the bones and to the lymph nodes. We discovered that the nucleotide-binding oligomerization domain leucine-rich region (NLR) pyrin domain containing family protein NLRP12 was among the genes whose expression was most different, transcriptome-wide, in bone and lymph node metastases. NLRP12 mRNA was present at significantly higher quantities in metastasis to the bone as compared to metastasis to the lymph nodes. Analysis of patient survival data revealed that expression of NLRP12 in primary tumors of the breast was correlated with recurrence-free survival, in lymph node positive patients but not in lymph node negative patients. NLRP12 has functions in transcriptional regulation of immune gene expression (2, 3) and in pathogen recognition of Yersinia pestis (4).

Transcriptional profiling of iPSC-derived neurons with reciprocal monogenic CNV in 3p26.3 region

2020 ◽  
pp. 10-11
Author(s):  
М.Е. Лопаткина ◽  
В.С. Фишман ◽  
М.М. Гридина ◽  
Н.А. Скрябин ◽  
Т.В. Никитина ◽  
...  
Keyword(s):  
Gene Expression ◽  
Copy Number ◽  
System Development ◽  
Transcriptional Profiling ◽  
Global Gene Expression ◽  
Nervous System Development ◽  
Number Variation ◽  
The Central Nervous System ◽  
Cntn6 Gene ◽  
Copy Number Changes

Проведен анализ генной экспрессии в нейронах, дифференцированных из индуцированных плюрипотентных стволовых клеток пациентов с идиопатическими интеллектуальными нарушениями и реципрокными хромосомными мутациями в регионе 3p26.3, затрагивающими единственный ген CNTN6. Для нейронов с различным типом хромосомных аберраций была показана глобальная дисрегуляция генной экспрессии. В нейронах с вариациями числа копий гена CNTN6 была снижена экспрессия генов, продукты которых вовлечены в процессы развития центральной нервной системы. The gene expression analysis of iPSC-derived neurons, obtained from patients with idiopathic intellectual disability and reciprocal microdeletion and microduplication in 3p26.3 region affecting the single CNTN6 gene was performed. The global gene expression dysregulation was demonstrated for cells with CNTN6 copy number variation. Gene expression in neurons with CNTN6 copy number changes was downregulated for genes, whose products are involved in the central nervous system development.

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