3955 results for "*geneti*"

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• Identification of genetic mutations characteristic for recurrence and metastasis of colon and rectal cancer.

  We collected the cancerous tissues of the primary and recurrence tumors from the same patient with recurrent / metastatic colorectal cancer, and the purpose of this study is to find the characteristics of recurrent / metastatic colorectal cancers by carrying out a "molecular profiling", mainly the exome sequence analysis of these tissues.

  Study JGAS000091

• Molecular analysis of diffuse cerebellar gliomas

  Among diffuse gliomas, oligodendrogliomas show relatively better prognosis, respond well to radiotherapy and chemotherapy, and seldom progress to very aggressive tumors. To elucidate the genetic and epigenetic background for such behavior and tumor evolution during tumor relapse, we comparatively analyzed 12 pairs of primary and recurrent oligodendrogliomas with 1p/19q-codeletion. Initial treatment for these patients was mostly chemotherapy alone. Temozolomide was used for 3, and procarbazine, nimustine and vincristine (PAV chemotherapy) were used for 7 patients. World Health Organization histological grade at recurrence was mostly stable; it was increased in 2, the same in 9, and decreased in 1 cases. Whole-exome sequencing demonstrated that the rate of shared mutation between the primary and recurrent tumors was relatively low, ranging from 3.2-57.9% (average, 33.3%), indicating a branched evolutionary pattern. The trunk alterations that existed throughout the course were restricted to IDH1 mutation, 1p/19q-codeletion, and TERT promoter mutation, and mutation of the known candidate tumor suppressor genes CIC and FUBP1 were not consistently observed between primary and recurrent tumors. Multiple sampling from different regions within a tumor showed marked intratumoral heterogeneity. Notably, in general, the number of mutations was not significantly different after recurrence, remaining under 100, and no hypermutator phenotype was observed. FUBP1 mutation, loss of chr. 9p21, and TCF12 mutation were among a few recurrent de novo alterations that were found at recurrence, indicating that these events were clonally selected at recurrence but were not enough to enhance malignancy. Genome-wide methylation status, measured by Illumina 450 K arrays, was stable between recurrence and the primary tumor. In summary, although oligodendroglioma displays marked mutational heterogeneity, histological malignant transformation accompanying events such as considerable increase in mutation number and epigenetic profile change were not observed at recurrence, indicating that noticeable temporal and spatial genetic heterogeneity in oligodendrogliomas does not result in rapid tumor progression.

  Study JGAS000106

• Identification of genetic mutations characteristic for recurrence and metastasis of gastric cancer.

  We collected the cancerous tissues of the primary and recurrence tumors from the same patient with recurrent / metastatic gastric cancer, and the purpose of this study is to find the characteristics of recurrent / metastatic gastric cancers by carrying out a "molecular profiling", mainly the exome sequence analysis of these tissues.

  Study JGAS000086

• Identification of genetic mutations characteristic for recurrence of serous ovarian cancer.

  Establishment of novel therapeutic strategy to overcome intractable cancer by molecular profiling of serous ovarian cancer

  Study JGAS000104

• Genome and gene analysis of gastrointestinal cancer and elucidation of its clinicopathological significance

  Cancer develops through the accumulation of genetic and epigenetic aberrations. To identify sequential molecular alterations that occur during the development of hepatocellular carcinoma (HCC), we molecularly compared 52 early and 108 overt HCC samples by genome sequencing. Gene mutations in the p53/RB1 pathway, WNT pathway, MLLs, SWI/SNF complexes, and AKT/PI3K pathway were common in HCC. In the early phase of all entities, TERT was the most frequently upregulated gene owing to diverse mechanisms. Despite frequent somatic mutations in driver genes, including CTNNB1 and TP53, early HCC was a separate molecular entity from overt HCC as each had a distinct expression profile. Notably, WNT target genes were not activated in early HCC, regardless of CTNNB1 mutation status, because ?-catenin did not translocate into the nucleus due to the E-Cadherin/?-catenin complex at the membrane. Conversely, WNT targets were definitively upregulated in overt HCC with CTNNB1 mutation associated with downregulation of CDH1 and hypomethylation of CpG islands in the target genes. Similarly, cell cycle genes downstream of the p53/RB pathway were upregulated only in overt HCC with TP53 and/or RB1 gene mutations associated with chromosomal deletion of 4q and/or 16q. Differing from the expression profile, HCC was epigenetically distinguished into four subclasses: normal-like methylation, global-hypomethylation (favorable prognosis), stem-like methylation (poor prognosis), and CpG island methylation. These methylation statuses were globally maintained through HCC progression. Taken together, additional molecular events besides driver gene mutations cooperatively contribute to transcriptional activation of downstream targets as HCC progresses, according to the methylation status of the associated genes.

  Study JGAS000233

• Cancer genomics for elucidation of molecular mechanisms of carcinogenecis and progression in lung cancer

  The objective of this project is to analyze genomic aberrations and gene expression changes such as mutations, deletions, amplifications, and hypermethylation in human lung cancer cells at the somatic cell level, and to contrast these with clinicopathological information to elucidate the molecular mechanisms and characteristics of lung cancer development and progression at the genetic level.

  Study JGAS000756

• DNA demethylation is associated with malignant progression of low-grade gliomas

  To elucidate the mechanisms of tumor progression is key to discovering strategies for treating patients with lower-grade glioma. Thus to characterize the changes in the molecular profile during malignant progression, we performed methylation array analysis (122 tumors), whole-exome sequencing (36 tumors and matched normal samples), and RNA sequencing (31 tumors). This cohort included 24 matched pairs of initial lower-grade gliomas and recurrent tumors, most of which showed malignant progression when they recurred. Nearly half of IDH-mutant glioblastomas that had progressed from lower-grade gliomas exhibited characteristic partial DNA demethylation in previously methylated genomic regions of their corresponding initial tumors, which had the glioma CpG island methylator phenotype (G-CIMP). In these glioblastomas, cell cycle-related genes were upregulated, RB and PI3K-AKT pathway genes were frequently altered. Notably, bioinformatics analysis revealed that late-replicating domain was significantly enriched in the demethylated regions that were mostly located in non-regulatory regions, suggesting that the loss of DNA methylation during malignant transformation may involve mainly passive demethylation due to a delay in maintenance of methylation during accelerated cell division. Nonetheless, a limited number of genes including IGF2BP3, which potentially drives cell proliferation, were presumed to be upregulated due to demethylation of their promoter. Thus, cell proliferation was further promoted by passive demethylation in the promoter region of these oncogenic genes. Our data indicated that demethylation of the G-CIMP profile found in a subset of recurrent gliomas reflects accelerated cell divisions accompanied by malignant transformation. Oncogenic genes activated by such epigenetic change represent potential therapeutic targets.

  Study JGAS000146

• Expression profiling of Gorlin iPSCs in the osteoblast induction culture

  In this study, we utilized human induced pluripotent stem cell (iPSC)-based models of the two diseases, named Gorlin syndrome and McCune Albright synfrome, to understand the roles of Hh signaling in osteogenesis, especially in mineralization. To examine which signaling pathways and genetic networks were affected by Gorlin syndrome-associated PTCH1 mutation in human osteoblastogenesis, we performed RNA sequencing (RNA-seq) analysis in the osteoblast induction culture of WT and Gorlin iPSCs.

  Study JGAS000218

• Gene expression of human Th17 cells before and after activation

  Although gene expression of human Th17 clones has been studies, to date, molecular mechanisms for human Th17 development remain unclear. We have analyzed gene expression of human Th17 cells before and after activation. Th17-cell clones from peripheral blood CD4 T cells cultured with LPS-stimulated dendritic cells derived from monocytes stimulated by TNF were established by a limited dilution method. One of the Th17 clones was proliferated significantly, and high percentages (>70%) of Th17 cells in the cultured cells were maintained by addition of monocytes, IL-1b, and IL-15. CD161+CXCR3- cells (CD161+Th17) in the cultures were sorted and purified up to approximately 97% of IL-17-producing cells after treatment with PMA/ionomycin. Furthermore, these cells were treated with TCR-stimuli, IL-1b, and IL-23 for 2 days, and IL-17-producing Th17 cells (active-Th17) detected by IL-17-catch-up antibodies were sorted. Total RNA sampled from 1x 106 CD161+Th17, active-Th17, na?ve CD4 T cells, or CXCR3+ Th1 cells from combined CD4 T and dendritic cell cultures was used for SAGE. SAGE was performed by using SOLID TM SAGETM kit with barcoding adaptor molecules (Applied Biosystems). DNA sequence was analyzed by using AB5500 Genetic Analyzer (Applied Biosystems), and gene expression was analyzed by using SOLID? SAGETM software (Applied Biosystems). Our data shows high levels of IL-17A-mRNA expression by active-Th17; however, but only slight expression by CD161+Th17. Therefore, the data could provide alteration of gene expression by Th17 cells before and after stimulation.

  Study JGAS000005

• Na?ve Treg-specific genomic DNA hypomethylation for autoimmune disease susceptibility

  Naturally occurring regulatory T (Treg) cells, which are specifically expressing the transcription factor FOXP3, CD25 and CTLA-4, are indispensable for the maintenance of immunological self-tolerance and homeostasis. Mutations of the FOXP3, CD25 and CTLA4 genes compromise the function of natural FOXP3+CD25+CD4+ Treg cells and cause severe autoimmune diseases showing Mendelian inheritance. Also, altered Treg-specific epigenetic changes, such as DNA hypomethylation and enhancer activation, impair the expression of these molecules in developing Treg cells, causing autoimmune diseases. It is obscure, however, whether Treg cells significantly contribute to the development of polygenic common autoimmune diseases (such as type 1 diabetes and rheumatoid arthritis), which afflict ~10% of the population. Recent genome-wide association study (GWAS) of common autoimmune diseases has revealed many autoimmune disease-associated single nucleotide polymorphisms (SNPs) in enhancer regions of immune cells, for example, in non-coding regions of T cell activation-associated genes such as CD25 and CTLA4. These findings, especially the involvement of common T-cell genes in the functions of both Treg cells and effector T cells, prompt one to ask whether autoimmune disease-associated causative SNPs impact on the functions of either disease-causing effector T cells or disease-suppressing Treg cells. Here, we have explored epigenetic profiles of human Treg and conventional T (Tconv) cells in na?ve or activated states, and found that autoimmune disease-associated SNPs are predominantly enriched in Treg-specific CpG demethylated regions (Treg-DRs), which were mostly included in Treg-specific super-enhancers. Treg-DRs are developmentally established in na?ve Treg cells before antigenic stimulation, distinct from activation-induced CpG hypomethylation in Treg or Tconv cells, and highly associated with Treg cell-specific transcriptional and epigenetic changes. Taken together, genetic variants affecting endogenous development of natural Treg cells and their Treg-intrinsic functions are causative of common autoimmune diseases, indicating natural Treg cells as a key target for their treatment and prevention.

  Study JGAS000145