Comprehensive Genetic Analysis of DGAT2 Mutations and Gene Expression Patterns in Human Cancers.
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ABSTRACT:
SUBMITTER: Graber M
PROVIDER: S-EPMC8389207 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe Caenorhabditis elegans genome encodes ten proteins that share sequence similarity with the Hedgehog signaling molecule through their C-terminal autoprocessing Hint/Hog domain. These proteins contain novel N-terminal domains, and C. elegans encodes dozens of additional proteins containing only these N-terminal domains. These gene families are called warthog, groundhog, ground-like and quahog, collectively called hedgehog (hh)-related genes. Previously, the expression pattern of seventeen genes was examined, which showed that they are primarily expressed in the ectoderm.ResultsWith the completion of the C. elegans genome sequence in November 2002, we reexamined and identified 61 hh-related ORFs. Further, we identified 49 hh-related ORFs in C. briggsae. ORF analysis revealed that 30% of the genes still had errors in their predictions and we improved these predictions here. We performed a comprehensive expression analysis using GFP fusions of the putative intergenic regulatory sequence with one or two transgenic lines for most genes. The hh-related genes are expressed in one or a few of the following tissues: hypodermis, seam cells, excretory duct and pore cells, vulval epithelial cells, rectal epithelial cells, pharyngeal muscle or marginal cells, arcade cells, support cells of sensory organs, and neuronal cells. Using time-lapse recordings, we discovered that some hh-related genes are expressed in a cyclical fashion in phase with molting during larval development. We also generated several translational GFP fusions, but they did not show any subcellular localization. In addition, we also studied the expression patterns of two genes with similarity to Drosophila frizzled, T23D8.1 and F27E11.3A, and the ortholog of the Drosophila gene dally-like, gpn-1, which is a heparan sulfate proteoglycan. The two frizzled homologs are expressed in a few neurons in the head, and gpn-1 is expressed in the pharynx. Finally, we compare the efficacy of our GFP expression effort with EST, OST and SAGE data.ConclusionNo bona-fide Hh signaling pathway is present in C. elegans. Given that the hh-related gene products have a predicted signal peptide for secretion, it is possible that they constitute components of the extracellular matrix (ECM). They might be associated with the cuticle or be present in soluble form in the body cavity. They might interact with the Patched or the Patched-related proteins in a manner similar to the interaction of Hedgehog with its receptor Patched.
| S-EPMC1636047 | biostudies-literature
Project description:BACKGROUND With the development of research on cancer genomics and microenvironment, a new era of oncology focusing on the complicated gene regulation of pan-cancer research and cancer immunotherapy is emerging. This study aimed to identify the common gene expression characteristics of multiple cancers - lung cancer, liver cancer, kidney cancer, cervical cancer, and breast cancer - and the potential therapeutic targets in public databases. MATERIAL AND METHODS Gene expression analysis of GSE42568, GSE19188, GSE121248, GSE63514, and GSE66272 in the GEO database of multitype cancers revealed differentially expressed genes (DEGs). Then, GO analysis, KEGG function, and path enrichment analyses were performed. Hub-genes were identified by using the degree of association of protein interaction networks. Moreover, the expression of hub-genes in cancers was verified, and hub-gene-related survival analysis was conducted. Finally, infiltration levels of tumor immune cells with related genes were explored. RESULTS We found 12 cross DEGs in the 5 databases (screening conditions: "adj p<0.05" and "logFC>2 or logFC<-2"). The biological processes of DEGs were mainly concentrated in cell division, regulation of chromosome segregation, nuclear division, cell cycle checkpoint, and mitotic nuclear division. Furthermore, 10 hub-genes were obtained using Cytoscape: TOP2A, ECT2, RRM2, ANLN, NEK2, ASPM, BUB1B, CDK1, DTL, and PRC1. The high expression levels of the 10 genes were associated with the poor survival of these multiple cancers, as well as ASPM, may be associated with immune cell infiltration. CONCLUSIONS Analysis of the common DEGs of multiple cancers showed that 10 hub-genes, especially ASPM and CDK1, can become potential therapeutic targets. This study can serve as a reference to understand the characteristics of different cancers, design basket clinical trials, and create personalized treatments.
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Project description:Previous studies studying mis-splicing mutations were based on exome data and thus our current knowledge is largely limited to exons and the canonical splice sites. To comprehensively characterise intronic mis-splicing mutations, we analysed 1134 pan-cancer whole genomes and transcriptomes together with 3022 normal control samples. The ratio-based splicing analysis resulted in 678 somatic intronic mutations, with 46% residing in deep introns. Among the 309 deep intronic single nucleotide variants, 245 altered core splicing codes, with 38% activating cryptic splice sites, 12% activating cryptic polypyrimidine tracts, and 36% and 12% disrupting authentic polypyrimidine tracts and branchpoints, respectively. All the intronic cryptic splice sites were created at pre-existing GT/AG dinucleotides or by GC-to-GT conversion. Notably, 85 deep intronic mutations indicated gain of splicing enhancers or loss of splicing silencers. We found that 64 tumour suppressors were affected by intronic mutations and blood cancers showed higher proportion of deep intronic mutations. In particular, a telomere maintenance gene, POT1, was recurrently mis-spliced by deep intronic mutations in blood cancers. We validated a pseudoexon activation involving a splicing silencer in POT1 by CRISPR/Cas9. Our results shed light on previously unappreciated mechanisms by which noncoding mutations acting on splicing codes in deep introns contribute to tumourigenesis.
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Project description:cDNA microarrays and a clustering algorithm were used to identify patterns of gene expression in human mammary epithelial cells growing in culture and in primary human breast tumors. Clusters of coexpressed genes identified through manipulations of mammary epithelial cells in vitro also showed consistent patterns of variation in expression among breast tumor samples. By using immunohistochemistry with antibodies against proteins encoded by a particular gene in a cluster, the identity of the cell type within the tumor specimen that contributed the observed gene expression pattern could be determined. Clusters of genes with coherent expression patterns in cultured cells and in the breast tumors samples could be related to specific features of biological variation among the samples. Two such clusters were found to have patterns that correlated with variation in cell proliferation rates and with activation of the IFN-regulated signal transduction pathway, respectively. Clusters of genes expressed by stromal cells and lymphocytes in the breast tumors also were identified in this analysis. These results support the feasibility and usefulness of this systematic approach to studying variation in gene expression patterns in human cancers as a means to dissect and classify solid tumors.
| S-EPMC17759 | biostudies-literature
Project description:Diacylglycerol acyltransferases (DGATs) catalyse the final step of the triacylglycerol (TAG) biosynthesis of the Kennedy pathway. Two major gene families have been shown to encode DGATs, DGAT1 (type-1) and DGAT2 (type-2). Both genes encode membrane-bound proteins, with no sequence homology to each other. In this study, the molecular cloning and characterization of a type-2 DGAT cDNA from olive is presented. Southern blot analysis showed that OeDGAT2 is represented by a single copy in the olive genome. Comparative transcriptional analysis revealed that DGAT1 and DGAT2 are developmentally regulated and share an overall overlapping but distinct transcription pattern in various tissues during vegetative growth. DGAT2 is highly expressed in mature or senescing olive tissues. In flowers, the expression of DGAT1 was almost undetectable, while DGAT2 transcripts accumulated at the later stages of both anther and ovary development. Differential gene regulation was also detected in the seed and mesocarp, two drupe compartments that largely differ in their functional roles and mode of lipid accumulation. DGAT1 appears to contribute for most of the TAG deposition in seeds, whereas, in the mesocarp, both DGAT1 and DGAT2 share an overlapping expression pattern. During the last stages of mesocarp growth, when TAGs are still accumulating, strong up-regulation of DGAT2 but a marked decline of DGAT1 transcript levels were detected. The present results show overlapping gene expression for olive DGATs during mesocarp growth, with a more prominent implication of DGAT2 in floral bud development and fruit ripening.
| S-EPMC3003803 | biostudies-literature
Project description:Mutations in 16 targetable oncogenic genes were examined using reverse transcription polymerase chain reaction (RT-PCR) and direct sequencing in 285 Chinese cervical cancers. Their clinicopathological relevance and prognostic significance was assessed. Ninety-two nonsynonymous somatic mutations were identified in 29.8% of the cancers. The mutation rates were as follows: PIK3CA (12.3%), KRAS (5.3%), HER2 (4.2%), FGFR3-TACC3 fusions (3.9%), PTEN (2.8%), FGFR2 (1.8%), FGFR3 (0.7%), NRAS (0.7%), HRAS (0.4%) and EGFR (0.4%). No mutations were detected in AKT1 or BRAF, and the fusions FGFR1-TACC1, EML4-ALK, CCDC6-RET and KIF5B-RET were not found in any of the cancers. RTK and RAS mutations were more common in non-squamous carcinomas than in squamous carcinomas (P=0.043 and P=0.042, respectively). RAS mutations were more common in young patients (<45 years) (13.7% vs. 7.7%, P=0.027). RTK mutations tended to be more common in young patients, whereas PIK3CA/PTEN/AKT mutations tended to be more common in old patients. RAS mutations were significantly associated with disease relapse. To our knowledge, this is the first comprehensive analysis of major targetable oncogenic mutations in a large cohort of cervical cancer cases. Our data reveal that a considerable proportion of patients with cervical cancers harbor known druggable mutations and might benefit from targeted therapy.
| S-EPMC4467127 | biostudies-literature
Project description:All the array experiments published in "Gene expression patterns in human liver cancers" by Chen X, et al. Hepatocellular carcinoma (HCC) is a leading cause of death worldwide. Using cDNA microarrays to characterize patterns of gene expression in HCC, we found consistent differences between the expression patterns in HCC compared with those seen in nontumor liver tissues. The expression patterns in HCC were also readily distinguished from those associated with tumors metastatic to liver. The global gene expression patterns intrinsic to each tumor were sufficiently distinctive that multiple tumor nodules from the same patient could usually be recognized and distinguished from all the others in the large sample set on the basis of their gene expression patterns alone. The distinctive gene expression patterns are characteristic of the tumors and not the patient; the expression programs seen in clonally independent tumor nodules in the same patient were no more similar than those in tumors from different patients. Moreover, clonally related tumor masses that showed distinct expression profiles were also distinguished by genotypic differences. Some features of the gene expression patterns were associated with specific phenotypic and genotypic characteristics of the tumors, including growth rate, vascular invasion, and p53 overexpression. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Keywords: Logical Set
2005-10-25 | GSE3500 | GEO
Project description:Both genetic and environmental factors are suggested to influence overweight and obesity risks. Although individual loci and genes have been frequently shown to be associated with body mass index (BMI), the overall interaction of these genes and their role in BMI remains underexplored. Data were collected in 90 healthy, predominately Caucasian participants (51% female) with a mean age of 26.00 ± 9.02 years. Whole blood samples were assayed by Affymetrix GeneChip Human Genome U133 Plus 2.0 Array. We integrated and analyzed the clinical and microarray gene expression data from those individuals to understand various systematic gene expression patterns underlying BMI. Conventional differential expression analysis identified seven genes RBM20, SEPT12, AX748233, SLC30A3, WTIP, CASP10, and OR12D3 associated with BMI. Weight gene co-expression network analysis among 4,647 expressed genes identified two gene modules associated with BMI. These two modules, with different extents of gene connectivity, are enriched for catabolic and muscle system processes respectively, and tend to be regulated by zinc finger transcription factors. A total of 246 hub genes were converted to non-hub genes, and 286 non-hub genes were converted to hub genes between normal and overweight individuals, revealing the network dynamics underlying BMI. A total of 28 three-way gene interactions were identified, suggesting the existence of high-order gene expression patterns underlying BMI. Our study demonstrated a variety of systematic gene expression patterns associated with BMI and thus provided novel understanding regarding the genetic factors for overweight and obesity risks on system levels.
| S-EPMC6520409 | biostudies-literature
Project description:To investigate the mechanisms of liver cancer progression and metastasis, we did expression profiling of human liver cancer and benign tissues. Keywords: gene expression array-based (RNA / in situ oligonucleotide)
2008-07-11 | GSE6222 | GEO
Project description:BackgroundN6-methyladenosine (m6A), the most abundant chemical modification on eukaryotic messenger RNA (mRNA), is modulated by three class of regulators namely "writers," "erasers," and "readers." Increasing studies have shown that aberrant expression of m6A regulators plays broad roles in tumorigenesis and progression. However, it is largely unknown regarding the expression regulation for RNA m6A regulators in human cancers.ResultsHere we characterized the expression profiles of RNA m6A regulators in 13 cancer types with The Cancer Genome Atlas (TCGA) data. We showed that METTL14, FTO, and ALKBH5 were down-regulated in most cancers, whereas YTHDF1 and IGF2BP3 were up-regulated in 12 cancer types except for thyroid carcinoma (THCA). Survival analysis further revealed that low expression of several m6A regulators displayed longer overall survival times. Then, we analyzed microRNA (miRNA)-regulated and DNA methylation-regulated expression changes of m6A regulators in pan-cancer. In total, we identified 158 miRNAs and 58 DNA methylation probes (DMPs) involved in expression regulation for RNA m6A regulators. Furthermore, we assessed the survival significance of those regulatory pairs. Among them, 10 miRNAs and 7 DMPs may promote cancer initiation and progression; conversely, 3 miRNA/mRNA pairs in kidney renal clear cell carcinoma (KIRC) may exert tumor-suppressor function. These findings are indicative of their potential prognostic values. Finally, we validated two of those miRNA/mRNA pairs (hsa-miR-1307-3p/METTL14 and hsa-miR-204-5p/IGF2BP3) that could serve a critical role for potential clinical application in KIRC patients.ConclusionsOur findings highlighted the importance of upstream regulation (miRNA and DNA methylation) governing m6A regulators' expression in pan-cancer. As a result, we identified several informative regulatory pairs for prognostic stratification. Thus, our study provides new insights into molecular mechanisms of m6A modification in human cancers.
| S-EPMC7946859 | biostudies-literature