scholarly journals Whole-genome sequencing of recurrent neuroblastoma reveals somatic mutations that affect key players in cancer progression and telomere maintenance

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Susanne Fransson ◽  
Angela Martinez-Monleon ◽  
Mathias Johansson ◽  
Rose-Marie Sjöberg ◽  
Caroline Björklund ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Cancer Progression ◽  
Cell Cycle Progression ◽  
Mapk Signaling ◽  
Telomere Maintenance ◽  
Whole Genome ◽  
Genomic Alterations ◽  
Cycle Progression

AbstractNeuroblastoma is the most common and deadly childhood tumor. Relapsed or refractory neuroblastoma has a very poor prognosis despite recent treatment advances. To investigate genomic alterations associated with relapse and therapy resistance, whole-genome sequencing was performed on diagnostic and relapsed lesions together with constitutional DNA from seven children. Sequencing of relapsed tumors indicates somatic alterations in diverse genes, including those involved in RAS-MAPK signaling, promoting cell cycle progression or function in telomere maintenance and immortalization. Among recurrent alterations, CCND1-gain, TERT-rearrangements, and point mutations in POLR2A, CDK5RAP, and MUC16 were shown in ≥ 2 individuals. Our cohort contained examples of converging genomic alterations in primary-relapse tumor pairs, indicating dependencies related to specific genetic lesions. We also detected rare genetic germline variants in DNA repair genes (e.g., BARD1, BRCA2, CHEK2, and WRN) that might cooperate with somatically acquired variants in these patients with highly aggressive recurrent neuroblastoma. Our data indicate the importance of monitoring recurrent neuroblastoma through sequential genomic characterization and that new therapeutic approaches combining the targeting of MAPK signaling, cell cycle progression, and telomere activity are required for this challenging patient group.

scholarly journals Spirulina Crude Protein Promotes the Migration and Proliferation in IEC-6 Cells by Activating EGFR/MAPK Signaling Pathway

Marine Drugs ◽  
2019 ◽  
Vol 17 (4) ◽  
pp. 205
Author(s):  
Su-Jin Jeong ◽  
Jeong-Wook Choi ◽  
Min-Kyeong Lee ◽  
Youn-Hee Choi ◽  
Taek-Jeong Nam
Keyword(s):  
Cell Cycle ◽  
Epithelial Cells ◽  
Signaling Pathway ◽  
Crude Protein ◽  
Cell Cycle Progression ◽  
Intestinal Epithelial Cells ◽  
Mapk Signaling ◽  
S Phase ◽  
Intestinal Epithelial ◽  
Cycle Progression

Spirulina is a type of filamentous blue-green microalgae known to be rich in nutrients and to have pharmacological effects, but the effect of spirulina on the small intestine epithelium is not well understood. Therefore, this study aims to investigate the proliferative effects of spirulina crude protein (SPCP) on a rat intestinal epithelial cells IEC-6 to elucidate the mechanisms underlying its effect. First, the results of wound-healing and cell viability assays demonstrated that SPCP promoted migration and proliferation in a dose-dependent manner. Subsequently, when the mechanisms of migration and proliferation promotion by SPCP were confirmed, we found that the epidermal growth factor receptor (EGFR) and mitogen-activated protein (MAPK) signaling pathways were activated by phosphorylation. Cell cycle progression from G0/G1 to S phase was also promoted by SPCP through upregulation of the expression levels of cyclins and cyclin-dependent kinases (Cdks), which regulate cell cycle progression to the S phase. Meanwhile, the expression of cyclin-dependent kinase inhibitors (CKIs), such as p21 and p27, decreased with SPCP. In conclusion, our results indicate that activation of EGFR and its downstream signaling pathway by SPCP treatment regulates cell cycle progression. Therefore, these results contribute to the research on the molecular mechanism for SPCP promoting the migration and proliferation of rat intestinal epithelial cells.

scholarly journals Regulation of Raf-1-dependent signaling during early Xenopus development.

1995 ◽  
Vol 15 (12) ◽  
pp. 6686-6693 ◽  
Author(s):  
A M MacNicol ◽  
A J Muslin ◽  
E L Howard ◽  
A Kikuchi ◽  
M C MacNicol ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Embryonic Cell ◽  
Cycle Progression ◽  
Mapk Activity ◽  
Cytostatic Factor ◽  
Differentiation And Proliferation

The Raf-1 gene product is activated in response to cellular stimulation by a variety of growth factors and hormones. Raf-1 activity has been implicated in both cellular differentiation and proliferation. We have examined the regulation of the Raf-1/MEK/MAP kinase (MAPK) pathway during embryonic development in the frog Xenopus laevis. We report that Raf-1, MEK, and MAPK activities are turned off following fertilization and remain undetectable up until blastula stages (stage 8), some 4 h later. Tight regulation of the Raf-1/MEK/MAPK pathway following fertilization is crucial for embryonic cell cycle progression. Inappropriate reactivation of MAPK activity by microinjection of oncogenic Raf-1 RNA results in metaphase cell cycle arrest and, consequently, embryonic lethality. Our findings demonstrate an absolute requirement, in vivo, for inactivation of the MAPK signaling pathway to allow normal cell cycle progression during the period of synchronous cell divisions which occur following fertilization. Further, we show that cytostatic factor effects are mediated through MEK and MAPK.

scholarly journals Regulation of Skp2 Expression and Activity and Its Role in Cancer Progression

2010 ◽  
Vol 10 ◽  
pp. 1001-1015 ◽  
Author(s):  
Chia-Hsin Chan ◽  
Szu-Wei Lee ◽  
Jing Wang ◽  
Hui-Kuan Lin
Keyword(s):  
Cell Cycle ◽  
Cancer Progression ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Protein Levels ◽  
Human Cancers ◽  
Attractive Therapeutic Target ◽  
Skp2 Protein ◽  
Regulation Of Cell Cycle ◽  
F Box Protein

The regulation of cell cycle entry is critical for cell proliferation and tumorigenesis. One of the key players regulating cell cycle progression is the F-box protein Skp2. Skp2 forms a SCF complex with Skp1, Cul-1, and Rbx1 to constitute E3 ligase through its F-box domain. Skp2 protein levels are regulated during the cell cycle, and recent studies reveal that Skp2 stability, subcellular localization, and activity are regulated by its phosphorylation. Overexpression of Skp2 is associated with a variety of human cancers, indicating that Skp2 may contribute to the development of human cancers. The notion is supported by various genetic mouse models that demonstrate an oncogenic activity of Skp2 and its requirement in cancer progression, suggesting that Skp2 may be a novel and attractive therapeutic target for cancers.

scholarly journals Identification of cancer-driver genes in focal genomic alterations from whole genome sequencing data

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Ho Jang ◽  
Youngmi Hur ◽  
Hyunju Lee
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Snp Array ◽  
Whole Genome Sequencing Data ◽  
Whole Genome ◽  
Sequencing Data ◽  
Genomic Alterations ◽  
Driver Genes ◽  
Cancer Driver ◽  
Cancer Driver Genes

Abstract DNA copy number alterations (CNAs) are the main genomic events that occur during the initiation and development of cancer. Distinguishing driver aberrant regions from passenger regions, which might contain candidate target genes for cancer therapies, is an important issue. Several methods for identifying cancer-driver genes from multiple cancer patients have been developed for single nucleotide polymorphism (SNP) arrays. However, for NGS data, methods for the SNP array cannot be directly applied because of different characteristics of NGS such as higher resolutions of data without predefined probes and incorrectly mapped reads to reference genomes. In this study, we developed a wavelet-based method for identification of focal genomic alterations for sequencing data (WIFA-Seq). We applied WIFA-Seq to whole genome sequencing data from glioblastoma multiforme, ovarian serous cystadenocarcinoma and lung adenocarcinoma, and identified focal genomic alterations, which contain candidate cancer-related genes as well as previously known cancer-driver genes.

scholarly journals Whole-genome sequencing of phenotypically distinct inflammatory breast cancers reveals similar genomic alterations to non-inflammatory breast cancers

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Xiaotong Li ◽  
Sushant Kumar ◽  
Arif Harmanci ◽  
Shantao Li ◽  
Robert R. Kitchen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Copy Number ◽  
Cancer Genome ◽  
Whole Genome ◽  
Breast Cancers ◽  
Genomic Alterations ◽  
Genomic Features ◽  
Clonal Architecture

Abstract Background Inflammatory breast cancer (IBC) has a highly invasive and metastatic phenotype. However, little is known about its genetic drivers. To address this, we report the largest cohort of whole-genome sequencing (WGS) of IBC cases. Methods We performed WGS of 20 IBC samples and paired normal blood DNA to identify genomic alterations. For comparison, we used 23 matched non-IBC samples from the Cancer Genome Atlas Program (TCGA). We also validated our findings using WGS data from the International Cancer Genome Consortium (ICGC) and the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We examined a wide selection of genomic features to search for differences between IBC and conventional breast cancer. These include (i) somatic and germline single-nucleotide variants (SNVs), in both coding and non-coding regions; (ii) the mutational signature and the clonal architecture derived from these SNVs; (iii) copy number and structural variants (CNVs and SVs); and (iv) non-human sequence in the tumors (i.e., exogenous sequences of bacterial origin). Results Overall, IBC has similar genomic characteristics to non-IBC, including specific alterations, overall mutational load and signature, and tumor heterogeneity. In particular, we observed similar mutation frequencies between IBC and non-IBC, for each gene and most cancer-related pathways. Moreover, we found no exogenous sequences of infectious agents specific to IBC samples. Even though we could not find any strongly statistically distinguishing genomic features between the two groups, we did find some suggestive differences in IBC: (i) The MAST2 gene was more frequently mutated (20% IBC vs. 0% non-IBC). (ii) The TGF β pathway was more frequently disrupted by germline SNVs (50% vs. 13%). (iii) Different copy number profiles were observed in several genomic regions harboring cancer genes. (iv) Complex SVs were more frequent. (v) The clonal architecture was simpler, suggesting more homogenous tumor-evolutionary lineages. Conclusions Whole-genome sequencing of IBC manifests a similar genomic architecture to non-IBC. We found no unique genomic alterations shared in just IBCs; however, subtle genomic differences were observed including germline alterations in TGFβ pathway genes and somatic mutations in the MAST2 kinase that could represent potential therapeutic targets.

scholarly journals Deep whole genome sequencing identifies recurrent genomic alterations in commonly-used breast cancer cell lines and patient derived xenograft models

2021 ◽  
Author(s):  
Niantao Deng ◽  
Andre Minoche ◽  
Kate Harvey ◽  
Andrei Goga ◽  
Alex Swarbrick
Keyword(s):  
Breast Cancer ◽  
Whole Genome Sequencing ◽  
Cell Lines ◽  
Cancer Cell ◽  
Genome Sequencing ◽  
Cancer Cell Lines ◽  
Whole Genome ◽  
Breast Cancers ◽  
Genomic Alterations ◽  
Pdx Models

Abstract BackgroundBreast cancer cell lines (BCCLs) and patient-derived xenografts (PDX) are the most frequently used models in breast cancer research. Despite their widespread usage, genome sequencing of these models is incomplete, with previous studies only focusing on targeted gene panels, whole exome or shallow whole genome sequencing. Deep whole genome sequencing is the most sensitive and accurate method to detect single nucleotide variants and indels, gene copy number and structural events such as gene fusions. ResultsHere we describe deep whole genome sequencing (WGS) of commonly used BCCL and PDX models using the Illumina X10 platform with an average ~ 60x coverage. We identify novel genomic alterations, including point mutations and genomic rearrangements at base-pair resolution, compared to previously available sequencing data. Through integrative analysis with publicly available functional screening data, we annotate new genomic features likely to be of biological significance. CSMD1 , previously identified as a tumor suppressor gene in various cancer types, including head and neck, lung and breast cancers, has been identified with deletion in 50% of our PDX models, suggesting an important role in aggressive breast cancers. ConclusionsOur WGS data provides a comprehensive genome sequencing resource of these models.

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